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https://www.readbyqxmd.com/read/29140514/idh-mutation-testing-in-gliomas-where-do-we-draw-the-line
#1
Farshad Nassiri, Gelareh Zadeh, Kenneth Aldape
No abstract text is available yet for this article.
November 11, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/29133704/survival-trends-in-glioma-experience-at-a-tertiary-care-centre
#2
Ratnadip Bose, Karanjit S Narang, Deepak Bhangale, Rishabh Kedia, Vikas Sharma, Ajaya N Jha
BACKGROUND: Even after decades of research in the field of gliomas, the overall prognosis is still quite dismal. Several factors have been proposed that affect the outcome and survival length of patients with a glioma. Here, we present a series of 471 patients, who underwent surgical resection of their glioma at a tertiary level neurosurgical centre. MATERIALS AND METHODS: We noted retrospective data of patients' age, histological tumor grade, and whether or not intraoperative magnetic resonance imaging (MRI) was used, and assessed the survival length of these patients from the day of surgery...
November 2017: Neurology India
https://www.readbyqxmd.com/read/29130549/concomitant-idh-wildtype-glioblastoma-and-idh1-mutant-anaplastic-astrocytoma-in-a-patient-with-constitutional-mismatch-repair-deficiency-syndrome
#3
Francesca Galuppini, Enrico Opocher, Uri Tabori, Isabella Mammi, Melissa Edwards, Britany Campbell, Jacalyn Kelly, Alessandra Viel, Michele Quaia, Francesca Rivieri, Domenico D'Avella, Antonella Arcella, Felice Giangaspero, Matteo Fassan, Marina Paola Gardiman
Constitutional mismatch repair deficiency (CMMRD) is a rare and often under-recognized tumour predisposition syndrome, presenting with both extracranial and malignant brain tumours that occur in children and/or young adults [1]. The genetic defects underlying this disease are biallelic germline mutations in one of the DNA mismatch repair (MMR) genes leading to a constitutional DNA repair defect that causes a cancer predisposition syndrome with early onset [2]. This mechanism is different from Lynch syndrome (LS) where a heterozygous germline loss-of-function mutation is observed and the patients are more prone to develop colon and genitourinary cancers as adults [1]...
November 12, 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/29128551/transplant-decisions-in-patients-with-myelofibrosis-should-mutations-be-the-judge
#4
REVIEW
Rachel B Salit, H Joachim Deeg
The prognosis of myeloproliferative neoplasms (MPN), including primary myelofibrosis (PMF), polycythemia vera (PV; post-PV MF) and essential thrombocythemia (ET; post-EMF) varies considerably, between these disorders as well as within each diagnosis. Molecular studies have identified "driver mutations", in JAK2, MPL1 and CALR, and additional somatic DNA mutations, including ASXL1, EZH2, IDH1/2 and SRSF2, that affect prognosis differentially. Patients with mutations in CALR (type1) have a better outlook than patients with mutations in JAK2 or MPL, while patients without any of the driver mutations (triple negative) have the shortest life expectancy...
November 8, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29126125/highly-specific-determination-of-idh-status-using-edited-in-vivo-magnetic-resonance-spectroscopy
#5
Francesca Branzoli, Anna Luisa Di Stefano, Laurent Capelle, Chris Ottolenghi, Romain Valabrègue, Dinesh K Deelchand, Franck Bielle, Chiara Villa, Bertrand Baussart, Stéphane Lehéricy, Marc Sanson, Malgorzata Marjanska
Background: Mutations in the isocitrate dehydrogenase (IDH) enzyme affects 40% of gliomas and represent a major diagnostic and prognostic marker. The goals of this study were to evaluate the performance of noninvasive magnetic resonance spectroscopy (MRS) methods to determine the IDH status of patients with brain gliomas through detection of the oncometabolite 2-hydroxyglutarate (2HG), and to compare performance of these methods with DNA sequencing and tissue 2HG analysis. Methods: Twenty-four subjects with suspected diagnosis of low grade glioma were included prospectively in the study...
November 6, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/29124520/seom-clinical-guideline-of-diagnosis-and-management-of-low-grade-glioma-2017
#6
J M Sepúlveda-Sánchez, J Muñoz Langa, M Á Arráez, J Fuster, A Hernández Laín, G Reynés, V Rodríguez González, E Vicente, M Vidal Denis, Ó Gallego
Diffuse infiltrating low-grade gliomas include oligodendrogliomas and astrocytomas, and account for about 5% of all primary brain tumors. Treatment strategies for these low-grade gliomas in adults have recently changed. The 2016 World Health Organization (WHO) classification has updated the definition of these tumors to include their molecular characterization, including the presence of isocitrate dehydrogenase (IDH) mutation and 1p/19p codeletion. In this new classification, the histologic subtype of grade II-mixed oligoastrocytoma has also been eliminated...
November 9, 2017: Clinical & Translational Oncology
https://www.readbyqxmd.com/read/29122763/prediction-of-idh1-mutation-and-1p-19q-codeletion-status-using-preoperative-mr-imaging-phenotypes-in-lower-grade-gliomas
#7
Y W Park, K Han, S S Ahn, S Bae, Y S Choi, J H Chang, S H Kim, S-G Kang, S-K Lee
BACKGROUND AND PURPOSE: WHO grade II gliomas are divided into three classes: isocitrate dehydrogenase (IDH)-wildtype, IDH-mutant and no 1p/19q codeletion, and IDH-mutant and 1p/19q-codeleted. Different molecular subtypes have been reported to have prognostic differences and different chemosensitivity. Our aim was to evaluate the predictive value of imaging phenotypes assessed with the Visually AcceSAble Rembrandt Images lexicon for molecular classification of lower grade gliomas. MATERIALS AND METHODS: MR imaging scans of 175 patients with lower grade gliomas with known IDH1 mutation and 1p/19q-codeletion status were included (78 grade II and 97 grade III) in the discovery set...
November 9, 2017: AJNR. American Journal of Neuroradiology
https://www.readbyqxmd.com/read/29105198/braf-v600e-tert-promoter-mutations-and-cdkn2a-b-homozygous-deletions-are-frequent-in-epithelioid-glioblastomas-a-histological-and-molecular-analysis-focusing-on-intratumoral-heterogeneity
#8
Nozomi Nakajima, Sumihito Nobusawa, Satoshi Nakata, Mitsutoshi Nakada, Tatsuya Yamazaki, Nozomi Matsumura, Kenichi Harada, Hadzki Matsuda, Nobuaki Funata, Shoichi Nagai, Hideo Nakamura, Atsushi Sasaki, Jiro Akimoto, Junko Hirato, Hideaki Yokoo
Epithelioid glioblastoma (E-GBM) is a rare aggressive variant of IDH-wildtype glioblastoma newly recognized in the 2016 World Health Organization classification, composed predominantly of monotonous, patternless sheets of round cells with laterally positioned nuclei and plump eosinophilic cytoplasm. Approximately 50% of E-GBM harbor BRAF V600E, which is much less frequently found in other types of glioblastomas. Most E-GBM are recognized as primary/de novo lesions; however, several E-GBM with co- or pre-existing lower-grade lesions have been reported...
November 4, 2017: Brain Pathology
https://www.readbyqxmd.com/read/29104858/idh-mutational-status-and-the-immune-system-in-gliomas-a-tale-of-two-tumors
#9
Bryan D Choi, William T Curry
No abstract text is available yet for this article.
October 2017: Translational Cancer Research
https://www.readbyqxmd.com/read/29097607/adaptive-evolution-of-the-gdh2-allosteric-domain-promotes-gliomagenesis-by-resolving-idh1-r132h-induced-metabolic-liabilities
#10
Matthew S Waitkus, Christopher J Pirozzi, Casey J Moure, Bill H Diplas, Landon J Hansen, Austin B Carpenter, Rui Yang, Zhaohui Wang, Brian O Ingram, Edward D Karoly, Robert P Mohney, Ivan Spasojeic, Roger E McLendon, Henry S Friedman, Yiping He, Darell D Bigner, Hai Yan
Hot-spot mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in a number of human cancers and confer a neomorphic enzyme activity that catalyzes the conversion of α-ketoglutarate (αKG) to the oncometabolite D-(2)-hydroxyglutarate (D2HG). In malignant gliomas, IDH1(R132H) expression induces widespread metabolic reprogramming, possibly requiring compensatory mechanisms to sustain the normal biosynthetic requirements of actively proliferating tumor cells. We used genetically engineered mouse models of glioma and quantitative metabolomics to investigate IDH1(R132H)-dependent metabolic reprogramming and its potential to induce biosynthetic liabilities that can be exploited for glioma therapy...
November 2, 2017: Cancer Research
https://www.readbyqxmd.com/read/29091765/low-grade-astrocytoma-mutations-in-idh1-p53-and-atrx-cooperate-to-block-differentiation-of-human-neural-stem-cells-via-repression-of-sox2
#11
Aram S Modrek, Danielle Golub, Themasap Khan, Devin Bready, Jod Prado, Christopher Bowman, Jingjing Deng, Guoan Zhang, Pedro P Rocha, Ramya Raviram, Charalampos Lazaris, James M Stafford, Gary LeRoy, Michael Kader, Joravar Dhaliwal, N Sumru Bayin, Joshua D Frenster, Jonathan Serrano, Luis Chiriboga, Rabaa Baitalmal, Gouri Nanjangud, Andrew S Chi, John G Golfinos, Jing Wang, Matthias A Karajannis, Richard A Bonneau, Danny Reinberg, Aristotelis Tsirigos, David Zagzag, Matija Snuderl, Jane A Skok, Thomas A Neubert, Dimitris G Placantonakis
Low-grade astrocytomas (LGAs) carry neomorphic mutations in isocitrate dehydrogenase (IDH) concurrently with P53 and ATRX loss. To model LGA formation, we introduced R132H IDH1, P53 shRNA, and ATRX shRNA into human neural stem cells (NSCs). These oncogenic hits blocked NSC differentiation, increased invasiveness in vivo, and led to a DNA methylation and transcriptional profile resembling IDH1 mutant human LGAs. The differentiation block was caused by transcriptional silencing of the transcription factor SOX2 secondary to disassociation of its promoter from a putative enhancer...
October 31, 2017: Cell Reports
https://www.readbyqxmd.com/read/29090344/the-role-of-mutant-idh1-and-idh2-inhibitors-in-the-treatment-of-acute-myeloid-leukemia
#12
REVIEW
Samah Nassereddine, Coen J Lap, Faysal Haroun, Imad Tabbara
For decades, researchers have looked into the pathophysiology of acute myeloid leukemia (AML). With the advances in molecular techniques, the two-hit hypothesis was replaced by a multi-hit model, which also emphasizes the importance of aberrant epigenetic regulation in the pathogenesis of AML. IDH1 and IDH2 are two isoforms of isocitrate dehydrogenase that perform crucial roles in cellular metabolism. Somatic mutations in either of these two genes impart a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert α-ketoglutarate (αKG) into the oncometabolite R2-hydroxyglutarate (R2-HG), which can competitively inhibit multiple αKG-dependent dioxygenases...
October 31, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/29089260/design-synthesis-and-biological-activity-of-3-pyrazine-2-yl-oxazolidin-2-ones-as-novel-potent-and-selective-inhibitors-of-mutant-isocitrate-dehydrogenase-1
#13
Tianfang Ma, Fangxia Zou, Stefan Pusch, Lijun Yang, Qihua Zhu, Yungen Xu, Yueqing Gu, Andreas von Deimling, Xiaoming Zha
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (α-KG) generating carbon dioxide and NADPH/NADH. Evidence suggests that the specific mutations in IDH1 are critical to the growth and reproduction of some tumor cells such as gliomas and acute myeloid leukemia, emerging as an attractive antitumor target. In order to discovery potent new mutant IDH1 inhibitors, we designed, synthesized and evaluated a series of allosteric mIDH1 inhibitors harboring the scaffold of 3-pyrazine-2-yl-oxazolidin-2-ones...
October 13, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29081442/glioblastoma-treatment-in-the-elderly
#14
Masaki Okada, Keisuke Miyake, Takashi Tamiya
Although current treatment advances prolong patient survival, treatment for glioblastoma (GBM) in the elderly has become an emerging issue. The definition of "elderly" differs across articles; GBM predominantly occurs at an age ≥65 years, and the prognosis worsens with increasing age. Regarding molecular markers, isocitrate dehydrogenase (IDH) mutations are less common in the elderly with GBM. Meanwhile, O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation has been identified in approximately half of patients with GBM...
October 30, 2017: Neurologia Medico-chirurgica
https://www.readbyqxmd.com/read/29071695/newer-strategies-for-the-management-of-low-grade-gliomas
#15
Karan Dixit, Jeffrey Raizer
Low-grade gliomas are infiltrative primary brain tumors that most commonly occur in young adults. They are relatively slow growing compared with high-grade gliomas. The World Health Organization classification system was updated in 2016 to define low-grade gliomas using molecular markers in addition to histology. IDH mutation is an independent marker associated with better outcomes. Management is individualized based on tumor histology, molecular characterization, and patient risk factors. Given the longer course and natural history of low-grade gliomas, the goals of treatment should be to prolong overall survival and minimize neurocognitive decline...
September 15, 2017: Oncology (Williston Park, NY)
https://www.readbyqxmd.com/read/29064021/targeting-idh1-and-idh2-mutations-in-acute-myeloid-leukemia
#16
REVIEW
Brittany Knick Ragon, Courtney D DiNardo
PURPOSE OF REVIEW: Over the past decade, the pathogenic role of mutations in isocitrate dehydrogenases (IDH) 1 and 2, affecting approximately 20% of patients with AML, has been defined, allowing for the development of specific therapeutic strategies for IDH-mutant AML. In this review, the landscape and progress of targeted therapeutics aimed at IDH mutations in AML and related myeloid malignancies will be described. RECENT FINDINGS: Since 2013, several mutant IDH-targeted inhibitors have been developed, and nearly a dozen clinical trials have opened specifically for IDH-mutant hematologic malignancies...
October 24, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/29057925/induction-of-synthetic-lethality-in-idh1-mutated-gliomas-through-inhibition-of-bcl-xl
#17
Georg Karpel-Massler, Chiaki Tsuge Ishida, Elena Bianchetti, Yiru Zhang, Chang Shu, Takashi Tsujiuchi, Matei A Banu, Franklin Garcia, Kevin A Roth, Jeffrey N Bruce, Peter Canoll, Markus D Siegelin
Certain gliomas often harbor a mutation in the activity center of IDH1 (R132H), which leads to the production of the oncometabolite 2-R-2-hydroxyglutarate (2-HG). In six model systems, including patient-derived stem cell-like glioblastoma cultures, inhibition of Bcl-xL induces significantly more apoptosis in IDH1-mutated cells than in wild-type IDH1 cells. Anaplastic astrocytoma samples with mutated IDH1 display lower levels of Mcl-1 than IDH1 wild-type tumors and specific knockdown of Mcl-1 broadly sensitizes glioblastoma cells to Bcl-xL inhibition-mediated apoptosis...
October 20, 2017: Nature Communications
https://www.readbyqxmd.com/read/29056515/in%C3%A2-vivo-imaging-of-glutamine-metabolism-to-the-oncometabolite-2-hydroxyglutarate-in-idh1-2-mutant-tumors
#18
Lucia Salamanca-Cardona, Hardik Shah, Alex J Poot, Fabian M Correa, Valentina Di Gialleonardo, Hui Lui, Vesselin Z Miloushev, Kristin L Granlund, Sui S Tee, Justin R Cross, Craig B Thompson, Kayvan R Keshari
The oncometabolite 2-hydroxyglutarate (2-HG) is a signature biomarker in various cancers, where it accumulates as a result of mutations in isocitrate dehydrogenase (IDH). The metabolic source of 2-HG, in a wide variety of cancers, dictates both its generation and also potential therapeutic strategies, but this remains difficult to access in vivo. Here, utilizing patient-derived chondrosarcoma cells harboring endogenous mutations in IDH1 and IDH2, we report that 2-HG can be rapidly generated from glutamine in vitro...
October 16, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/29054837/altered-metabolic-landscape-in-idh-mutant-gliomas%C3%A2-affects-phospholipid-energy-and-oxidative-stress-pathways
#19
Fred Fack, Saverio Tardito, Guillaume Hochart, Anais Oudin, Liang Zheng, Sabrina Fritah, Anna Golebiewska, Petr V Nazarov, Amandine Bernard, Ann-Christin Hau, Olivier Keunen, William Leenders, Morten Lund-Johansen, Jonathan Stauber, Eyal Gottlieb, Rolf Bjerkvig, Simone P Niclou
Heterozygous mutations in NADP-dependent isocitrate dehydrogenases (IDH) define the large majority of diffuse gliomas and are associated with hypermethylation of DNA and chromatin. The metabolic dysregulations imposed by these mutations, whether dependent or not on the oncometabolite D-2-hydroxyglutarate (D2HG), are less well understood. Here, we applied mass spectrometry imaging on intracranial patient-derived xenografts of IDH-mutant versus IDH wild-type glioma to profile the distribution of metabolites at high anatomical resolution in situ This approach was complemented by in vivo tracing of labeled nutrients followed by liquid chromatography-mass spectrometry (LC-MS) analysis...
October 20, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29053887/low-foxg1-and-high-olig-2-labelling-indices-define-a-prognostically-favorable-subset-in-idh-mutant-gliomas
#20
Sarah Schäfer, Felix Behling, Marco Skardelly, Marilin Koch, Ines Ott, Frank Paulsen, Ghazaleh Tabatabai, Jens Schittenhelm
AIMS: Previous data suggest that expression of transcription factors FoxG1 and Olig-2 can separate hotspot H3F3A-mutant tumors in pediatric glioma. We evaluated their prognostic potential and feasibility for identifying H3F3A-mutant tumors among IDH-mutant/wildtype gliomas. METHODS: Immunohistochemistry of FoxG1/Olig-2 and ATRX in 471 cases of diffuse gliomas and molecular determination of IDH, H3F3A, MGMT and 1p/19 codeletion status. RESULTS: Mean percentage of FoxG1 positive tumor cells increased from 17% in WHO grade II to over 21% in grade III to 37% in grade IV tumors, while mean Olig-2 indices decreased from 29% to 28% to 17% respectively...
October 20, 2017: Neuropathology and Applied Neurobiology
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