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Idh mutant

Daisuke Kuga, Nobuhiro Hata, Yojiro Akagi, Takeo Amemiya, Yuhei Sangatsuda, Ryusuke Hatae, Koji Yoshimoto, Masahiro Mizoguchi, Koji Iihara
BACKGROUND: We previously reported a favorable outcome in a case series of patients with oligodendrogliomas treated with upfront chemotherapy; however, their progression free survival (PFS) was relatively short considering their long-term overall survival (OS). This suggests that salvage treatments after progression were effective. However, the clinical impact of salvage treatments on outcomes of patients with recurrent oligodendrogliomas has not been precisely investigated. METHODS: Our case series included 28 patients with newly diagnosed isocitrate dehydrogenase (IDH)-mutant and 1p/19q-codeleted oligodendroglial tumors treated with upfront procarbazine+nimustine+vincristine (PAV)...
March 15, 2018: World Neurosurgery
Akane Yamamichi, Fumiharu Ohka, Kosuke Aoki, Hiromichi Suzuki, Akira Kato, Masaki Hirano, Kazuya Motomura, Kuniaki Tanahashi, Lushun Chalise, Sachi Maeda, Toshihiko Wakabayashi, Yukinari Kato, Atsushi Natsume
The IDH-mutant and 1p/19q co-deletion (1p19q codel) provides significant diagnostic and prognostic value in lower-grade gliomas. As ATRX mutation and 1p19q codel are mutually exclusive, ATRX immunohistochemistry (IHC) may substitute for 1p19q codel, but this has not been comprehensively examined. In the current study, we performed ATRX-IHC in 78 gliomas whose ATRX statuses were comprehensively determined by whole exome sequencing. Among the 60 IHC-positive and 18 IHC-negative cases, 86.7 and 77.8% were ATRX-wildtype and ATRX-mutant, respectively...
March 17, 2018: Brain Tumor Pathology
Julie J Miller, Wolfgang Wick
The majority of World Health Organization grade II and grade III gliomas harbor heterozygous mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1), and tumors with an IDH wild-type status show molecular features of a glioblastoma and simply may constitute a separate disease entity. This discovery has led to a profound shift in the way that gliomas are classified and, consequently, how treatment decisions are made. We will review the current understanding of IDH- mutant gliomagenesis and the preclinical models being used to investigate the underlying biology of these tumors and to explore new therapeutic options for these patients...
February 2018: Seminars in Neurology
Michael Karsy, Jian Guan, L Eric Huang
OBJECTIVE Gliomas are one of the most common types of primary brain tumors. Recent studies have supported the importance of key genetic alterations, including isocitrate dehydrogenase (IDH) mutations and 1p19q codeletion, in glioma prognosis. Mutant IDH produces 2-hydroxyglutarate from α-ketoglutarate, a key metabolite of the Krebs cycle. The mitochondrial pyruvate carrier (MPC) is composed of MPC1 and MPC2 subunits and is functionally essential for the Krebs cycle. The authors sought to explore the impact of MPC1 and MPC2 expression on patient prognosis...
March 16, 2018: Journal of Neurosurgery
Tie Li, Christopher D Cox, Byram Ozer, Nhung T Nguyen, Huytram N Nguyen, Thomas J Lai, Sichen Li, Fei Liu, Harley I Kornblum, Linda M Liau, Phioanh Leia Nghiemphu, Timothy F Cloughesy, Albert Lai
Mutant isocitrate dehydrogenase (IDH) 1/2 converts α-ketoglutarate (α-KG) to D-2 hydroxyglutarate (D-2-HG), a putative oncometabolite that can inhibit α-KG dependent enzymes, including ten-eleven translocation methylcytosine dioxygenase (TET) DNA demethylases. We recently established that miRNAs are components of the IDH1 mutant-associated glioma CpG island methylator phenotype (G-CIMP), and specifically identified MIR148A as a tumor-suppressive miRNA within G-CIMP. However, the precise mechanism by which mutant IDH induces hypermethylation of MIR148A and other G-CIMP promoters remains to be elucidated...
March 15, 2018: Molecular Cancer Research: MCR
Guillermo Montalban-Bravo, Courtney D DiNardo
Isocitrate dehydrogenases (IDHs) are enzymes involved in multiple metabolic and epigenetic cellular processes. Mutations in IDH1 or IDH2 are detected in approximately 20% of patients with acute myeloid leukemia (AML) and induce amino acid changes in conserved residues resulting in neomorphic enzymatic function and production of an oncometabolite, 2-hydroxyglutarate (R-2-HG). This leads to DNA hypermethylation, aberrant gene expression, cell proliferation and abnormal differentiation. IDH mutations diversely affect prognosis of patients with AML based on the location of the mutation and other co-occurring genomic abnormalities...
March 15, 2018: Future Oncology
Debajyoti Chatterjee, Bishan Dass Radotra, Narendra Kumar, Rakesh Kumar Vasishta, Sunil Kumar Gupta
Background: According to the current World Health Organization (WHO) classification of central nervous system (CNS) tumors (2016), histological diagnosis of gliomas should be supplemented by molecular information. This study was carried out to determine the frequency of isocitrate dehydrogenase 1 ( IDH 1), ATRX , and BRAF V600E mutations in different grade astrocytomas and their prognostic value. Methods: Eighty cases of astrocytoma (15 pilocytic astrocytoma, 25 diffuse astrocytoma, 15 anaplastic astrocytoma, and 25 glioblastoma) with follow-up information were analyzed using immunohistochemistry for IDH1 mutant protein, ATRX, p53, and BRAF...
2018: Surgical Neurology International
José E Velázquez Vega, Daniel J Brat
Recent advances in molecular pathology have reshaped the practice of brain tumor diagnostics. The classification of gliomas has been restructured with the discovery of isocitrate dehydrogenase (IDH) 1/2 mutations in the vast majority of lower grade infiltrating gliomas and secondary glioblastomas (GBM), with IDH-mutant astrocytomas further characterized by TP53 and ATRX mutations. Whole-arm 1p/19q codeletion in conjunction with IDH mutations now define oligodendrogliomas, which are also enriched for CIC, FUBP1, PI3K, NOTCH1, and TERT-p mutations...
March 8, 2018: Advances in Anatomic Pathology
Rémi Longuespée, Annika K Wefers, Elena De Vita, Aubry K Miller, David E Reuss, Wolfgang Wick, Christel Herold-Mende, Mark Kriegsmann, Peter Schirmacher, Andreas von Deimling, Stefan Pusch
All isocitrate dehydrogenase (IDH) mutant solid neoplasms exhibit highly elevated levels of D-2-hydroxyglutarate (D-2HG). Detection of 2HG in tumor tissues currently is performed by gas or liquid chromatography-mass spectrometry (GC- or LC-MS) or biochemical detection. While these methods are highly accurate, a considerable amount of time for tissue preparation and a relatively high amount of tissue is required for testing. We here present a rapid approach to detect 2HG in brain tumor tissue based on matrix-assisted laser desorption ionization - time of flight mass spectrometry (MALDI-TOF)...
March 2, 2018: Acta Neuropathologica Communications
Anteneh M Feyissa, Gregory A Worrell, William O Tatum, Deependra Mahato, Benjamin H Brinkmann, Steven S Rosenfeld, Karim ReFaey, Perry S Bechtle, Alfredo Quinones-Hinojosa
OBJECTIVE: To examine the relationship between high-frequency oscillations (HFOs) and the presence of preoperative seizures, World Health Organization tumor grade, and isocitrate dehydrogenase 1 (IDH1) mutational status in gliomas. METHODS: We retrospectively studied intraoperative electrocorticography recorded in 16 patients with brain tumor (12 presenting with seizures) who underwent awake craniotomy and surgical resection between September 2016 and June 2017...
February 28, 2018: Neurology
M Unterrrainer, I Winkelmann, B Suchorska, A Giese, V Wenter, F W Kreth, J Herms, P Bartenstein, J C Tonn, N L Albert
PURPOSE: For the clinical evaluation of O-(2-18 F-fluoroethyl)-L-tyrosine (18 F-FET) PET images, the use of standard summation images obtained 20-40 min after injection is recommended. However, early summation images obtained 5-15 min after injection have been reported to allow better differentiation between low-grade glioma (LGG) and high-grade glioma (HGG) by capturing the early18 F-FET uptake peak specific for HGG. We compared early and standard summation images with regard to delineation of the PET-derived biological tumour volume (BTV) in correlation with the molecular genetic profile according the updated 2016 WHO classification...
February 27, 2018: European Journal of Nuclear Medicine and Molecular Imaging
Christine Marosi
No abstract text is available yet for this article.
February 21, 2018: EBioMedicine
T Gambichler, I Rüddel, S Hessam, F G Bechara, E Stockfleth, L Schmitz
BACKGROUND: Koebnerized non-melanoma skin cancer following skin trauma represents a rare and obscure event. OBJECTIVES: To study molecularpathological parameters in koebnerized squamous cell carcinomas (K-SCCs) occurring after complete tumour removal. METHODS: We assessed two patients with multiple sclerosis who were on treatment with dimethylfumarate (DMF) preceded by long-term azathioprine therapy. Both patients rapidly developed several K-SCCs following histopathologically proven complete excision of cutaneous SCCs...
February 25, 2018: Journal of the European Academy of Dermatology and Venereology: JEADV
Dan Ye, Kun-Liang Guan, Yue Xiong
Isocitrate dehydrogenases (IDH1/2) are frequently mutated in multiple types of human cancer, resulting in neomorphic enzymes that convert α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). The current view on the mechanism of IDH mutation holds that 2-HG acts as an antagonist of α-KG to competitively inhibit the activity of α-KG-dependent dioxygenases, including those involved in histone and DNA demethylation. Recent studies have implicated 2-HG in activities beyond epigenetic modification. Multiple enzymes have been discovered that lack mutations but that can nevertheless produce 2-HG promiscuously under hypoxic or acidic conditions...
February 2018: Trends in Cancer
Serah Choi, Yao Yu, Matthew R Grimmer, Michael Wahl, Susan M Chang, Joseph F Costello
Low-grade gliomas cause considerable morbidity and most will recur after initial therapy. At recurrence, low-grade gliomas can undergo transformation to high-grade gliomas (grade III or grade IV), which are associated with worse prognosis. Temozolomide (TMZ) provides survival benefit in patients with glioblastomas (GBMs) but its value in patients with low-grade gliomas is less clear. A subset of TMZ-treated, IDH-mutant, low-grade astrocytomas recur as more malignant tumors with thousands of de novo, coding mutations bearing a signature of TMZ-induced hypermutation...
February 14, 2018: Neuro-oncology
Martin Hasselblatt, Mohammed Jaber, David Reuss, Oliver Grauer, Annkatrin Bibo, Stephanie Terwey, Uta Schick, Heinrich Ebel, Thomas Niederstadt, Walter Stummer, Andreas von Deimling, Werner Paulus
The histological and molecular features and even the mere existence of diffuse astrocytoma, IDH-wildtype, remain unclear. We therefore examined 212 diffuse astrocytomas (grade II WHO) in adults using IDH1(R132H) immunohistochemistry followed by IDH1/IDH2 sequencing and neuroimaging review. DNA methylation status and copy number profiles were assessed by Infinium HumanMethylation450k BeadChip. Only 25/212 patients harbored tumors without IDH1/IDH2 hotspot mutations and without contrast enhancement. By DNA methylation profiling, 10/25 tumors were classified as glioblastoma, IDH-wildtype, and an additional 7 cases could not be classified using methylome analysis, but showed genetic characteristics of glioblastoma...
February 9, 2018: Journal of Neuropathology and Experimental Neurology
Hanumantha Rao Madala, Surendra R Punganuru, Viswanath Arutla, Subhasis Misra, T J Thomas, Kalkunte S Srivenugopal
Isocitrate dehydrogenases 1 and 2 (IDH1,2), the key Krebs cycle enzymes that generate NADPH reducing equivalents, undergo heterozygous mutations in >70% of low- to mid-grade gliomas and ~20% of acute myeloid leukemias (AMLs) and gain an unusual new activity of reducing the α-ketoglutarate (α-KG) to D-2 hydroxyglutarate (D-2HG) in a NADPH-consuming reaction. The oncometabolite D-2HG, which accumulates >35 mM, is widely accepted to drive a progressive oncogenesis besides exacerbating the already increased oxidative stress in these cancers...
February 11, 2018: Cancers
Min Zhou, Yue Zhou, Huijun Liao, Benjamin C Rowland, Xiangquan Kong, Nils D Arvold, David A Reardon, Patrick Y Wen, Alexander P Lin, Raymond Y Huang
Background: Isocitrate dehydrogenase (IDH) mutations result in abnormal accumulation of 2-hydroxyglutarate (2HG) in gliomas that can be detected by MRS. We examined the diagnostic accuracy of 2HG single-voxel spectroscopy (SVS) and chemical shift imaging (CSI) in both newly-diagnosed and post-treatment settings. Methods: Long-TE (97 ms) SVS and CSI were acquired in 85 subjects, including a discovery cohort of 39 patients who had postoperative residual or recurrent glioma with confirmed IDH-mutation status and 6 normal volunteers, a prospective preoperative validation cohort of 24 patients with newly-diagnosed brain mass, and a prospective recurrent-lesion validation cohort of 16 previously-treated IDH-mutant glioma patients with suspected tumor recurrence...
February 9, 2018: Neuro-oncology
Z Wang, X Liu, Z Wang, Z Bao, W Zhang, C Zhang, T Jiang
BACKGROUND: Isocitrate dehydrogenase (IDH) mutation is the initiating event that defines major clinical and prognostic classes of gliomas, but the potential mechanisms have not been well interpreted yet. The main objective of the current study was to better understand the underlying biology of IDH mutant gliomas as captured by gene expression profiles. METHODS: RNA sequencing data of WHO grade II-IV gliomas from the Chinese Glioma Genome Atlas (CGGA, N=325) were used to assess differentially expressed genes between IDH mutant and wild type gliomas and to construct a gene expression-based classifier to detect IDH mutant samples with high sensitivity and specificity...
February 12, 2018: Current Molecular Medicine
Fuxin Han, Jinsong Zhang, Shanbo Ma, Xiaoyan Chen, Weiping Liu, Xiaosheng He, Zhou Fei, Yangang Wang
To evaluate the prognostic significance of the altered expression of capicua transcriptional repressor (CIC) in isocitrate dehydrogenase ( IDH )-mutant oligodendroglial tumors, a cohort of 54 IDH -mutant oligodendroglial tumors (designated as the Xijing cohort) were examined by immunohistochemistry (IHC), and two public expression data sets from The Cancer Genome Atlas (TCGA; n=265) and the Gene Expression Omnibus (GEO; n=45) were analyzed in the present study. The prognostic value was evaluated by survival analysis and Cox hazards models...
February 2018: Oncology Letters
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