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Diffuse intrinsic pontine glioma ( DIPG )

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https://www.readbyqxmd.com/read/30254491/combined-use-of-cdk4-6-and-mtor-inhibitors-induce-synergistic-growth-arrest-of-diffuse-intrinsic-pontine-glioma-cells-via-mutual-downregulation-of-mtorc1-activity
#1
Daniel J Asby, Clare L Killick-Cole, Lisa J Boulter, William Gb Singleton, Claire A Asby, Marcella J Wyatt, Neil U Barua, Alison S Bienemann, Steven S Gill
Background: Diffuse intrinsic pontine glioma (DIPG) is a lethal type of pediatric brain tumor that is resistant to conventional chemotherapies. Palbociclib is a putative novel DIPG treatment that restricts the proliferation of rapidly dividing cancer cells via selective inhibition of cyclin-dependent kinase (CDK) 4 and CDK6. However, implementing palbociclib as a monotherapy for DIPG is unfeasible, as CDK4/6 inhibitor resistance is commonplace and palbociclib does not readily cross the blood-brain barrier (BBB) or persist in the central nervous system...
2018: Cancer Management and Research
https://www.readbyqxmd.com/read/30192215/tumor-dissemination-through-surgical-tracts-in-diffuse-intrinsic-pontine-glioma
#2
Maria-Jesus Lobon-Iglesias, Vicente Santa-Maria Lopez, Patricia Puerta Roldan, Santiago Candela-Cantó, Monica Ramos-Albiac, Marta Gomez-Chiari, Stephanie Puget, Stephanie Bolle, Liliana Goumnerova, Mark W Kieran, Ofelia Cruz, Jacques Grill, Andres Morales La Madrid
OBJECTIVE Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive and lethal brainstem tumor in children. In the 1980s, routine biopsy at presentation was abandoned since it was claimed "unnecessary" for diagnosis. In the last decade, however, several groups have reincorporated this procedure as standard of care or in the context of clinical trials. Expert neurosurgical teams report no mortality and acceptable morbidity, and no relevant complications have been previously described. The aim of this study was to review needle tract dissemination as a potential complication in DIPG...
September 7, 2018: Journal of Neurosurgery. Pediatrics
https://www.readbyqxmd.com/read/30174560/measuring-tumor-metabolism-in-pediatric-diffuse-intrinsic-pontine-glioma-using-hyperpolarized-carbon-13-mr-metabolic-imaging
#3
Adam W Autry, Rintaro Hashizume, C David James, Peder E Z Larson, Daniel B Vigneron, Ilwoo Park
Objective: The purpose of this study was to demonstrate the feasibility of using hyperpolarized carbon-13 (13 C) metabolic imaging with [1-13 C]-labeled pyruvate for evaluating real-time in vivo metabolism of orthotopic diffuse intrinsic pontine glioma (DIPG) xenografts. Materials and Methods: 3D 13 C magnetic resonance spectroscopic imaging (MRSI) data were acquired on a 3T scanner from 8 rats that had been implanted with human-derived DIPG cells in the brainstem and 5 healthy controls, following injection of 2...
2018: Contrast Media & Molecular Imaging
https://www.readbyqxmd.com/read/30169876/characterization-of-the-immune-microenvironment-of-diffuse-intrinsic-pontine-glioma-implications-for-development-of-immunotherapy
#4
Nicole A P Lieberman, Kole DeGolier, Heather M Kovar, Amira Davis, Virginia Hoglund, Jeffrey Stevens, Conrad Winter, Gail Deutsch, Scott N Furlan, Nicholas A Vitanza, Sarah E S Leary, Courtney A Crane
Background: Diffuse Intrinsic Pontine Glioma (DIPG) is a uniformly fatal CNS tumor diagnosed in 300 American children per year. Radiation is the only effective treatment and extends overall survival to a median of 11 months. Due to its location in the brainstem, DIPG tumors cannot be surgically resected. Immunotherapy has the ability to target tumor cells specifically, however, little is known about the tumor microenvironment in DIPGs. We sought to characterize infiltrating immune cells and immunosuppressive factor expression in pediatric low- and high-grade gliomas and DIPG...
August 28, 2018: Neuro-oncology
https://www.readbyqxmd.com/read/30138731/population-based-study-determining-predictors-of-cancer-specific-mortality-and-survival-in-pediatric-high-grade-brainstem-glioma
#5
Russell Maxwell, Andrew S Luksik, Tomas Garzon-Muvdi, Wuyang Yang, Judy Huang, Chetan Bettegowda, George I Jallo, Stephanie A Terezakis, Mari L Groves
BACKGROUND: Pediatric high-grade brainstem gliomas are aggressive tumors with dismal prognoses. Large-scale studies are needed to further characterize these tumors and determine factors influencing cancer-specific mortality and survival at varying time points. METHODS: We used the SEER (Surveillance Epidemiology and End Results) database to conduct a population-based study of pediatric patients with histologically confirmed anaplastic astrocytoma or glioblastoma tumors located within the brainstem...
August 20, 2018: World Neurosurgery
https://www.readbyqxmd.com/read/30124166/bioinformatics-analysis-of-microarray-data-to-reveal-the-pathogenesis-of-diffuse-intrinsic-pontine-glioma
#6
Li Wei, Fei He, Wen Zhang, Wenhua Chen, Bo Yu
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is the main cause of pediatric brain tumor death. This study was designed to identify key genes associated with DIPG. METHODS: The gene expression profile GSE50021, which consisted of 35 pediatric DIPG samples and 10 normal brain samples, was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified by limma package. Functional and pathway enrichment analyses were performed by the DAVID tool...
August 20, 2018: Biological Research
https://www.readbyqxmd.com/read/30101054/histone-h3-mutations-in-cancer
#7
REVIEW
Yi Ching Esther Wan, Jiaxian Liu, Kui Ming Chan
Histone modifications are one form of epigenetic information that relate closely to gene regulation. Aberrant histone methylation caused by alteration in chromatin-modifying enzymes has long been implicated in cancers. More recently, recurrent histone mutations have been identified in multiple cancers and have been shown to impede histone methylation. All three histone mutations (H3K27M, H3K36M, and H3G34V/R) identified result in amino acid substitution at/near a lysine residue that is a target of methylation...
2018: Current Pharmacology Reports
https://www.readbyqxmd.com/read/30072503/evaluation-of-11-c-methionine-pet-and-anatomic-mri-associations-in-diffuse-intrinsic-pontine-glioma
#8
Christopher Tinkle, Elizabeth Duncan, Mikhail Doubrovin, Yuanyuan Han, Yimei Li, Hyun Kim, Alberto Broniscer, Scott E Snyder, Thomas E Merchant, Barry L Shulkin
The role of metabolic imaging in the diagnosis, treatment, and response assessment of diffuse intrinsic pontine glioma (DIPG) is poorly-defined. We investigated the uptake of 11 C-methionine (11 C-MET) in pediatric patients with newly diagnosed DIPG and evaluated the associations of 11 C-MET positron emission tomography (PET) metrics with conventional MRI indices and survival outcomes. Methods: Twenty-two patients with newly diagnosed DIPG were prospectively enrolled on an IRB-approved investigational study of 11 C-MET-PET...
August 2, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/30061363/melk-inhibition-in-diffuse-intrinsic-pontine-glioma
#9
Michaël H Meel, Mark C de Gooijer, Miriam Guillén Navarro, Piotr Waranecki, Marjolein Breur, Levi Buil, Laurine E Wedekind, Jos W R Twisk, Jan Koster, Rintaro Hashizume, Eric H Raabe, Angel Montero Carcaboso, Marianna Bugiani, Olaf van Tellingen, Dannis G van Vuurden, Gertjan J L Kaspers, Esther Hulleman
PURPOSE: Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brain tumor, for which no effective therapeutic options currently exist. We here determined the potential of inhibition of the maternal embryonic leucine zipper kinase (MELK) for the treatment of DIPG. EXPERIMENTAL DESIGN: We evaluated the antitumor efficacy of the small molecule MELK inhibitor OTSSP167 in vitro in patient-derived DIPG cultures, and identified the mechanism of action of MELK inhibition in DIPG by RNA sequencing of treated cells...
July 30, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/30049282/medulloblastoma-therapy-generates-risk-of-a-poorly-prognostic-h3-wild-type-subgroup-of-diffuse-intrinsic-pontine-glioma-a-report-from-the-international-dipg-registry
#10
Hunter C Gits, Maia Anderson, Stefanie Stallard, Drew Pratt, Becky Zon, Christopher Howell, Chandan Kumar-Sinha, Pankaj Vats, Katayoon Kasaian, Daniel Polan, Martha Matuszak, Daniel E Spratt, Marcia Leonard, Tingting Qin, Lili Zhao, James Leach, Brooklyn Chaney, Nancy Yanez Escorza, Jacob Hendershot, Blaise Jones, Christine Fuller, Sarah Leary, Ute Bartels, Eric Bouffet, Torunn I Yock, Patricia Robertson, Rajen Mody, Sriram Venneti, Arul M Chinnaiyan, Maryam Fouladi, Nicholas G Gottardo, Carl Koschmann
With improved survivorship in medulloblastoma, there has been an increasing incidence of late complications. To date, no studies have specifically addressed the risk of radiation-associated diffuse intrinsic pontine glioma (DIPG) in medulloblastoma survivors. Query of the International DIPG Registry identified six cases of DIPG with a history of medulloblastoma treated with radiotherapy. All patients underwent central radiologic review that confirmed a diagnosis of DIPG. Six additional cases were identified in reports from recent cooperative group medulloblastoma trials (total n = 12; ages 7 to 21 years)...
July 26, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/30018882/beyond-the-blood-brain-barrier-the-importance-of-central-nervous-system-cns-pharmacokinetics-for-the-treatment-of-cns-tumors-including-diffuse-intrinsic-pontine-glioma
#11
REVIEW
Katherine Elizabeth Warren
Over the past decade, we have made considerable progress in establishing diffuse intrinsic pontine glioma (DIPG) as a disease entity and developing preclinical tools to interrogate potential therapeutics. However, translation to improved clinical outcomes in children with DIPG has not yet been realized. This is in part due to difficulties encountered in delivering active drugs adequately to the tumor site. However, most preclinical evaluations gloss over the fundamental concepts of central nervous system (CNS) pharmacokinetics and requirements needed to optimize drug delivery and exposure and translate this into efficacious therapy...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29967352/functional-diversity-and-cooperativity-between-subclonal-populations-of-pediatric-glioblastoma-and-diffuse-intrinsic-pontine-glioma-cells
#12
Mara Vinci, Anna Burford, Valeria Molinari, Ketty Kessler, Sergey Popov, Matthew Clarke, Kathryn R Taylor, Helen N Pemberton, Christopher J Lord, Alice Gutteridge, Tim Forshew, Diana Carvalho, Lynley V Marshall, Elizabeth Y Qin, Wendy J Ingram, Andrew S Moore, Ho-Keung Ng, Saoussen Trabelsi, Dorra H'mida-Ben Brahim, Natacha Entz-Werle, Stergios Zacharoulis, Sucheta Vaidya, Henry C Mandeville, Leslie R Bridges, Andrew J Martin, Safa Al-Sarraj, Christopher Chandler, Mariona Sunol, Jaume Mora, Carmen de Torres, Ofelia Cruz, Angel M Carcaboso, Michelle Monje, Alan Mackay, Chris Jones
The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies...
August 2018: Nature Medicine
https://www.readbyqxmd.com/read/29954445/non-inflammatory-tumor-microenvironment-of-diffuse-intrinsic-pontine-glioma
#13
Grant L Lin, Surya Nagaraja, Mariella G Filbin, Mario L Suvà, Hannes Vogel, Michelle Monje
Diffuse intrinsic pontine glioma (DIPG) is a universally fatal malignancy of the childhood central nervous system, with a median overall survival of 9-11 months. We have previously shown that primary DIPG tissue contains numerous tumor-associated macrophages, and substantial work has demonstrated a significant pathological role for adult glioma-associated macrophages. However, work over the past decade has highlighted many molecular and genomic differences between pediatric and adult high-grade gliomas. Thus, we directly compared inflammatory characteristics of DIPG and adult glioblastoma (GBM)...
June 28, 2018: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29932419/h3-3k27m-mutant-proteins-reprogram-epigenome-by-sequestering-the-prc2-complex-to-poised-enhancers
#14
Dong Fang, Haiyun Gan, Liang Cheng, Jeong-Heon Lee, Hui Zhou, Jann N Sarkaria, David J Daniels, Zhiguo Zhang
Expression of histone H3.3K27M mutant proteins in human diffuse intrinsic pontine glioma (DIPG) results in a global reduction of tri-methylation of H3K27 (H3K27me3), and paradoxically, H3K27me3 peaks remain at hundreds of genomic loci, a dichotomous change that lacks mechanistic insights. Here, we show that the PRC2 complex is sequestered at poised enhancers, but not at active promoters with high levels of H3.3K27M proteins, thereby contributing to the global reduction of H3K27me3. Moreover, the levels of H3...
June 22, 2018: ELife
https://www.readbyqxmd.com/read/29904623/cdk4-6-and-pdgfra-signaling-as-therapeutic-targets-in-diffuse-intrinsic-pontine-glioma
#15
REVIEW
Christine Hoeman, Chen Shen, Oren J Becher
Diffuse intrinsic pontine gliomas (DIPGs) are incurable childhood brain tumors, whereby the standard of care is focal radiation, a treatment that provides temporary relief for most patients. Surprisingly, decades of clinical trials have failed to identify additional therapies that can prolong survival in this disease. In this conference manuscript, we discuss how genetic engineered mouse modeling techniques with the use of a retroviral gene delivery system can help dissect the complex pathophysiology of this disease...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29802243/live-cell-single-molecule-dynamics-of-pcg-proteins-imposed-by-the-dipg-h3-3k27m-mutation
#16
Roubina Tatavosian, Huy Nguyen Duc, Thao Ngoc Huynh, Dong Fang, Benjamin Schmitt, Xiaodong Shi, Yiming Deng, Christopher Phiel, Tingting Yao, Zhiguo Zhang, Haobin Wang, Xiaojun Ren
Over 80% of diffuse intrinsic pontine gliomas (DIPGs) harbor a point mutation in histone H3.3 where lysine 27 is substituted with methionine (H3.3K27M); however, how the mutation affects kinetics and function of PcG proteins remains elusive. We demonstrate that H3.3K27M prolongs the residence time and search time of Ezh2, but has no effect on its fraction bound to chromatin. In contrast, H3.3K27M has no effect on the residence time of Cbx7, but prolongs its search time and decreases its fraction bound to chromatin...
May 25, 2018: Nature Communications
https://www.readbyqxmd.com/read/29760046/dual-hdac-and-pi3k-inhibition-abrogates-nf%C3%AE%C2%BAb-and-foxm1-mediated-dna-damage-response-to-radiosensitize-pediatric-high-grade-gliomas
#17
Sharmistha Pal, David Kozono, Xiaodong Yang, Wojciech Fendler, Whitney Fitts, Jing Ni, John A Alberta, Jean Zhao, Kevin X Liu, Jie Bian, Nathalene Truffaux, William A Weiss, Adam C Resnick, Pratiti Bandopadhayay, Keith L Ligon, Steven G DuBois, Sabine Mueller, Dipanjan Chowdhury, Daphne A Haas-Kogan
Aberrant chromatin remodeling and activation of the PI3K pathway have been identified as important mediators of pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) pathogenesis. As inhibition of these pathways are promising therapeutic avenues and radiation is the only modality to prolong survival of patients with DIPG, we sought to explore radiosensitizing functions of such inhibition and to explore mechanisms of action of such agents. Here, we demonstrate that combined treatment with radiotherapy and CUDC-907, a novel first-in-class dual inhibitor of histone deacetylases (HDAC) and PI3K, evokes a potent cytotoxic response in pHGG and DIPG models...
July 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29755954/immune-response-generated-with-the-administration-of-autologous-dendritic-cells-pulsed-with-an-allogenic-tumoral-cell-lines-lysate-in-patients-with-newly-diagnosed-diffuse-intrinsic-pontine-glioma
#18
Daniel Benitez-Ribas, Raquel Cabezón, Georgina Flórez-Grau, Mari Carmen Molero, Patricia Puerta, Antonio Guillen, Sonia Paco, Angel M Carcaboso, Vicente Santa-Maria Lopez, Ofelia Cruz, Carmen de Torres, Noelia Salvador, Manel Juan, Jaume Mora, Andres Morales La Madrid
Background and objective: Diffuse intrinsic pontine glioma (DIPG) is a lethal brainstem tumor in children. Dendritic cells (DCs) have T-cell stimulatory capacity and, therefore, potential antitumor activity for disease control. DCs vaccines have been shown to reactivate tumor-specific T cells in both clinical and preclinical settings. We designed a phase Ib immunotherapy (IT) clinical trial with the use of autologous dendritic cells (ADCs) pulsed with an allogeneic tumors cell-lines lysate in patients with newly diagnosed DIPG after irradiation (radiation therapy)...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29753957/brainstem-blood-brain-barrier-disruption-using-focused-ultrasound-a-demonstration-of-feasibility-and-enhanced-doxorubicin-delivery
#19
Saira Alli, Carlyn A Figueiredo, Brian Golbourn, Nesrin Sabha, Megan Yijun Wu, Andrew Bondoc, Amanda Luck, Daniel Coluccia, Colin Maslink, Christian Smith, Heiko Wurdak, Kullervo Hynynen, Meaghan O'Reilly, James T Rutka
Magnetic Resonance Image-guided Focused Ultrasound (MRgFUS) has been used to achieve transient blood brain barrier (BBB) opening without tissue injury. Delivery of a targeted ultrasonic wave causes an interaction between administered microbubbles and the capillary bed resulting in enhanced vessel permeability. The use of MRgFUS in the brainstem has not previously been shown but could provide value in the treatment of tumours such as Diffuse Intrinsic Pontine Glioma (DIPG) where the intact BBB has contributed to the limited success of chemotherapy...
July 10, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29750396/a-phase-1-2-dose-finding-safety-and-activity-study-of-cabazitaxel-in-pediatric-patients-with-refractory-solid-tumors-including-tumors-of-the-central-nervous-system
#20
Peter E Manley, Tanya Trippett, Amy A Smith, Margaret E Macy, Sarah E S Leary, Jessica Boklan, Kenneth J Cohen, Stewart Goldman, Lindsay B Kilburn, Girish Dhall, Jeanne Devin, Cynthia E Herzog, Sonia Partap, Floris Fauchet, Emmy Badreddine, John P Bernard, Susan N Chi
BACKGROUND: This phase 1/2 study (NCT01751308) evaluated cabazitaxel in pediatric patients. Phase 1 determined the maximum tolerated dose (MTD) in patients with recurrent/refractory solid tumors, including central nervous system (CNS) tumors. Phase 2 evaluated activity in pediatric recurrent high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). PROCEDURE: In phase 1, a 3 + 3 dose-escalation study design was followed. Cabazitaxel was administered at a starting dose of 20 mg/m2 ...
September 2018: Pediatric Blood & Cancer
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