Intraoperative Assessment of IDH Mutation Status and Tumor Invasioni in Glioma

2021 ◽  
Vol 156 (Supplement_1) ◽  
pp. S141-S142
Author(s):  
H Brown ◽  
R Chen ◽  
R Cooks ◽  
D Garcia ◽  
K Chaichana ◽  
...  
Keyword(s):  
Unmet Need ◽  
Lipid Profiles ◽  
Ionization Mass ◽  
Idh Mutation ◽  
Fresh Tissue ◽  
Mutation Status ◽  
Ms Analysis ◽  
Idh Mutations ◽  
Desi Ms ◽  
Sensitivity Specificity

Abstract Introduction/Objective Maximizing surgical resection in gliomas, while avoiding compromising non-infiltrated tissue, is associated with survival benefit. Current methodologies are suboptimal in providing rapid, intraoperative molecular characterization of tissue. We address this unmet need by using desorption electrospray ionization mass spectrometry (DESI-MS) for the intraoperative molecular assessment of gliomas. Methods/Case Report This prospective study uses intraoperative DESI-MS analysis of fresh tissue to evaluate IDH mutations via 2-hydroxyglutarate intensity and TCP via measurement of N-acetylaspartic acid (NAA) intensity and characteristic lipid profiles in less than three minutes. Blinded review of the tissue smears by a neuropathologist is used to validate IDH mutation status and TCP estimates. Results (if a Case Study enter NA) Presently, 529 biopsies from 85 enrolled patients have been collected and analyzed at two institutions. TCP assessment based on NAA intensity in 203 biopsies at the first institution yielded sensitivity, specificity, and accuracy values of 91, 76, and 83%, whereas TCP estimates via characteristic lipid profiles yielded 76, 85, and 81%, respectively. Assessment of IDH mutation status of 71 core biopsies yielded sensitivity, specificity, and accuracy values of 89, 100, and 94%. Ongoing validation of the methodology is being performed at a second institution, where we have collected 282 biopsies from 36 patients. IDH mutation assessment of the first 15 patients indicate 100% sensitivity, specificity, and accuracy. Conclusion This study represents the first and largest study using DESI-MS for the intraoperative evaluation of IDH status and TCP measurement in gliomas. Prospectively, we propose to modify our DESI-MS system to allow estimation of IDH mutation status and TCP in surgical cavities without the need for a biopsy by placing a surgical material along the margin and transferring material from the blot to a microscope slide prior to DESI-MS analysis. We envision molecular analysis by DESI-MS as a complementary technique to histopathology capable of providing additional clinical information in near real-time.

PATH-13. INTRAOPERATIVE EVALUATION OF IDH MUTATION STATUS AND TUMOR INVASION IN GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi117-vi117
Author(s):  
Hannah Brown ◽  
Diogo Garcia ◽  
Rong Chen ◽  
Mark Jentoft ◽  
Erik Middlebrooks ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Lipid Profiles ◽  
Ionization Mass ◽  
Idh Mutation ◽  
Mutation Status ◽  
Intraoperative Evaluation ◽  
Ms Analysis ◽  
Idh Mutations ◽  
Desi Ms ◽  
Sensitivity Specificity

Abstract BACKGROUND Intraoperative detection of residual tumor and isocitrate dehydrogenase (IDH) mutations can assist in maximizing surgical resection beyond contrast enhancing margins and guide intraoperative surgical decision making for glioma patients. We aimed to evaluate the use of desorption electrospray ionization-mass spectrometry (DESI-MS) for intraoperative assessment of IDH mutations and estimation of tumor cell percentage (TCP). METHODS This is a prospective study using intraoperative DESI-MS analysis of freshly obtained tissue samples to evaluate IDH mutations via 2-hydroxyglutarate (2-HG) intensity and TCP via measurement of N-acetylaspartic acid (NAA) intensity and characteristic lipid profiles. These IDH mutation and TCP estimates were subsequently validated by a senior neuropathologist. RESULTS A total of 247 biopsies from a 49-patient study were previously collected and analyzed at Indiana University. Assessment of TCP in 203 margin and core biopsies based on NAA intensity yielded sensitivity, specificity, and accuracy values of 91, 76, and 83%, whereas TCP assessment based on characteristic lipid profiles yielded 76, 85, and 81%, respectively. Assessment of IDH mutation status of 71 core biopsies yielded sensitivity, specificity, and accuracy values of 89, 100, and 94%. Further validation of the methodology is being performed in an ongoing collaboration with Mayo Clinic-Jacksonville, where we have collected 178 biopsies from 24 patients. Preliminary results of IDH mutation assessments indicate 100% sensitivity, specificity, and accuracy. DISCUSSION/CONCLUSION We present a novel system to allow intraoperative evaluation of IDH status and to guide surgical resection by TCP measurement from tissue biopsies. Prospectively, we propose to modify our DESI-MS system by placing a surgical material (e.g. cottonoid) along the surgical margin and transferring material from the blot to a microscope slide prior to DESI-MS analysis. This will allow the retention of the spatial distribution of diagnostic molecules while analyzing a wall of the surgical cavity without the need for biopsy.

Intraoperative assessment of isocitrate dehydrogenase mutation status in human gliomas using desorption electrospray ionization–mass spectrometry

2020 ◽  
Vol 132 (1) ◽  
pp. 180-187 ◽  
Author(s):  
Clint M. Alfaro ◽  
Valentina Pirro ◽  
Michael F. Keating ◽  
Eyas M. Hattab ◽  
R. Graham Cooks ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Electrospray Ionization ◽  
Isocitrate Dehydrogenase ◽  
Tumor Resection ◽  
Desorption Electrospray Ionization ◽  
Extent Of Resection ◽  
Ionization Mass ◽  
Idh Mutation ◽  
Mutation Status ◽  
Desi Ms

OBJECTIVEThe authors describe a rapid intraoperative ambient ionization mass spectrometry (MS) method for determining isocitrate dehydrogenase (IDH) mutation status from glioma tissue biopsies. This method offers new glioma management options and may impact extent of resection goals. Assessment of the IDH mutation is key for accurate glioma diagnosis, particularly for differentiating diffuse glioma from other neoplastic and reactive inflammatory conditions, a challenge for the standard intraoperative diagnostic consultation that relies solely on morphology.METHODSBanked glioma specimens (n = 37) were analyzed by desorption electrospray ionization–MS (DESI-MS) to develop a diagnostic method to detect the known altered oncometabolite in IDH-mutant gliomas, 2-hydroxyglutarate (2HG). The method was used intraoperatively to analyze tissue smears obtained from glioma patients undergoing resection and to rapidly diagnose IDH mutation status (< 5 minutes). Fifty-one tumor core biopsies from 25 patients (14 wild type [WT] and 11 mutant) were examined and data were analyzed using analysis of variance and receiver operating characteristic curve analysis.RESULTSThe optimized DESI-MS method discriminated between IDH-WT and IDH-mutant gliomas, with an average sensitivity and specificity of 100%. The average normalized DESI-MS 2HG signal was an order of magnitude higher in IDH-mutant glioma than in IDH-WT glioma. The DESI 2HG signal intensities correlated with independently measured 2HG concentrations (R2 = 0.98). In 1 case, an IDH1 R132H–mutant glioma was misdiagnosed as a demyelinating condition by frozen section histology during the intraoperative consultation, and no resection was performed pending the final pathology report. A second craniotomy and tumor resection was performed after the final pathology provided a diagnosis most consistent with an IDH-mutant glioblastoma. During the second craniotomy, high levels of 2HG in the tumor core biopsies were detected.CONCLUSIONSThis study demonstrates the capability to differentiate rapidly between IDH-mutant gliomas and IDH-WT conditions by DESI-MS during tumor resection. DESI-MS analysis of tissue smears is simple and can be easily integrated into the standard intraoperative pathology consultation. This approach may aid in solving differential diagnosis problems associated with low-grade gliomas and could influence intraoperative decisions regarding extent of resection, ultimately improving patient outcome. Research is ongoing to expand the patient cohort, systematically validate the DESI-MS method, and investigate the relationships between 2HG and tumor heterogeneity.

scholarly journals Inhibition of PARP Sensitizes Chondrosarcoma Cell Lines to Chemo- and Radiotherapy Irrespective of the IDH1 or IDH2 Mutation Status

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1918 ◽  
Author(s):  
Sanne Venneker ◽  
Alwine B. Kruisselbrink ◽  
Inge H. Briaire-de Bruijn ◽  
Yvonne de Jong ◽  
Andre J. van Wijnen ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cell Lines ◽  
Dna Methyltransferase ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Parp Inhibition ◽  
Idh Mutation ◽  
Mutation Status ◽  
Chondrosarcoma Cell ◽  
Idh Mutations

Chondrosarcomas are chemo- and radiotherapy resistant and frequently harbor mutations in isocitrate dehydrogenase (IDH1 or IDH2), causing increased levels of D-2-hydroxyglutarate (D-2-HG). DNA repair defects and synthetic lethality with poly(ADP-ribose) polymerase (PARP) inhibition occur in IDH mutant glioma and leukemia models. Here we evaluated DNA repair and PARP inhibition, alone or combined with chemo- or radiotherapy, in chondrosarcoma cell lines with or without endogenous IDH mutations. Chondrosarcoma cell lines treated with the PARP inhibitor talazoparib were examined for dose–response relationships, as well as underlying cell death mechanisms and DNA repair functionality. Talazoparib was combined with chemo- or radiotherapy to evaluate potential synergy. Cell lines treated long term with an inhibitor normalizing D-2-HG levels were investigated for synthetic lethality with talazoparib. We report that talazoparib sensitivity was variable and irrespective of IDH mutation status. All cell lines expressed Ataxia Telangiectasia Mutated (ATM), but a subset was impaired in poly(ADP-ribosyl)ation (PARylation) capacity, homologous recombination, and O-6-methylguanine-DNA methyltransferase (MGMT) expression. Talazoparib synergized with temozolomide or radiation, independent of IDH1 mutant inhibition. This study suggests that talazoparib combined with temozolomide or radiation are promising therapeutic strategies for chondrosarcoma, irrespective of IDH mutation status. A subset of chondrosarcomas may be deficient in nonclassical DNA repair pathways, suggesting that PARP inhibitor sensitivity is multifactorial in chondrosarcoma.

scholarly journals Pharmacoresistant seizures and IDH mutation in low grade gliomas

2021 ◽  
Author(s):  
Carlos Eduardo Correia ◽  
Yoshie Umemura ◽  
Jessica R Flynn ◽  
Anne S Reiner ◽  
Edward K Avila
Keyword(s):  
Tumor Resection ◽  
Incidence Rates ◽  
P Value ◽  
Low Grade ◽  
Idh Mutation ◽  
Wild Type ◽  
Mutation Status ◽  
Low Grade Gliomas ◽  
Idh1 R132h ◽  
Idh Mutations

Abstract Purpose Many low-grade gliomas (LGG) harbor isocitrate dehydrogenase (IDH) mutations. Although IDH mutation is known to be epileptogenic, the rate of refractory seizures in LGG with IDH mutation vs wild-type had not been previously compared. We therefore compared seizure pharmacoresistance in IDH-mutated and wild-type LGGs. Methods Single-institution retrospective study of patients with histologic proven LGG, known IDH mutation status, seizures, and ≥ 2 neurology clinic encounters. Seizure history was followed until histological high-grade transformation or death. Seizures requiring ≥ 2 changes in anti-epileptic drugs were considered pharmacoresistant. Incidence rates of pharmacoresistant seizures were estimated using competing risks methodology. Results Of 135 patients, 25 patients (19%) had LGGs classified as IDH wild-type. Of those with IDH mutation, 104 (94.5%) were IDH1 R132H; only six were IDH2 R172K. 120 patients (89%) had tumor resection and 14 (10%) had biopsy. Initial post-surgical management included observation (64%), concurrent chemoradiation (23%), chemotherapy alone (9%), and radiotherapy alone (4%). Seizures became pharmacoresistant in 24 IDH-mutated patients (22%) and in 3 IDH wild-type patients (12%). The 4-year cumulative incidence of intractable seizures was 17.6% (95% CI: 10.6%-25.9%) in IDH-mutated and 11% (95% CI: 1.3%-32.6%) in IDH wild-type LGG (Gray’s P-value= 0.26). Conclusions 22% of the IDH-mutated patients developed pharmacoresistant seizures, compared to 12% of the IDH wild-type tumors.The likelihood of developing pharmacoresistant seizures in patients with LGG-related epilepsy is independent to IDH mutation status, however, IDH-mutated tumors were approximately twice as likely to experience LGG-related pharmacoresistant seizures.

Impact of adjuvant temozolomide and IDH mutation status among patients with anaplastic astrocytoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2025-2025
Author(s):  
Sani Haider Kizilbash ◽  
Caterina Giannini ◽  
Jesse S Voss ◽  
Paul A. Decker ◽  
Robert B. Jenkins ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Multivariable Analysis ◽  
Cox Proportional Hazards ◽  
Adjuvant Radiation ◽  
Significant Prognostic Factor ◽  
Idh Mutation ◽  
Mutation Status ◽  
Kaplan Meier ◽  
Idh Mutations ◽  
Paraffin Block

2025 Background: Although adjuvant radiation has demonstrated a clear survival benefit in anaplastic astrocytomas (AA), the role of concurrent temozolomide (TMZ) remains controversial. Methods: All adult patients diagnosed with AA from 2001 to 2011 and treated with standard doses of adjuvant radiation were identified retrospectively using the neuro-oncology database at the Mayo Clinic (Rochester, MN). Clinical data was extracted from the electronic medical record. IDH mutation status was also determined by obtaining either IDH1R132H immunostain on existing unstained slides or paraffin block sections, or by sequencing. Cumulative survival probabilities were estimated using the Kaplan-Meier method. Univariable and multivariable Cox proportional hazards regression models were fit to compare patients who did/did not receive TMZ. Results: 218 patients were identified that met inclusion criteria. 34 patients were excluded due to missing data on adjuvant chemotherapy. 146 patients had received adjuvant TMZ while 38 had not. Of these, IDH mutation status was determined on 124 patients who received TMZ and 33 of those who had not. The median duration of follow up was 36.4 months. On univariable analysis, adjuvant TMZ demonstrated a trend towards improved median survival from 35.2 to 53.1 months (p=0.06). As an independent variable, patients with IDH mutations had longer median survivals (111.7 months) when compared to IDH wild-type patients (23.3 months) (p<0.001). On multivariable analysis, five-year-survival was significantly impacted by receipt of adjuvant TMZ (HR = 0.56, p=0.03) and IDH mutation status remained a significant prognostic factor (HR = 0.19, p < 0.001) (see Table). Conclusions: IDH mutation strongly predicts a favorable outcome in patients with AA. Secondarily, concurrent TMZ is also associated with improved survival in patients with AA who are receiving adjuvant radiotherapy. [Table: see text]

scholarly journals Multicenter DSC–MRI-Based Radiomics Predict IDH Mutation in Gliomas

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3965
Author(s):  
Georgios C. Manikis ◽  
Georgios S. Ioannidis ◽  
Loizos Siakallis ◽  
Katerina Nikiforaki ◽  
Michael Iv ◽  
...  
Keyword(s):  
External Validation ◽  
Model Development ◽  
Dynamic Susceptibility ◽  
Idh Mutation ◽  
Dynamic Susceptibility Contrast ◽  
Cohen’S Kappa ◽  
Mutation Status ◽  
Cohen's Kappa ◽  
Dsc Mri ◽  
Idh Mutations

To address the current lack of dynamic susceptibility contrast magnetic resonance imaging (DSC–MRI)-based radiomics to predict isocitrate dehydrogenase (IDH) mutations in gliomas, we present a multicenter study that featured an independent exploratory set for radiomics model development and external validation using two independent cohorts. The maximum performance of the IDH mutation status prediction on the validation set had an accuracy of 0.544 (Cohen’s kappa: 0.145, F1-score: 0.415, area under the curve-AUC: 0.639, sensitivity: 0.733, specificity: 0.491), which significantly improved to an accuracy of 0.706 (Cohen’s kappa: 0.282, F1-score: 0.474, AUC: 0.667, sensitivity: 0.6, specificity: 0.736) when dynamic-based standardization of the images was performed prior to the radiomics. Model explainability using local interpretable model-agnostic explanations (LIME) and Shapley additive explanations (SHAP) revealed potential intuitive correlations between the IDH–wildtype increased heterogeneity and the texture complexity. These results strengthened our hypothesis that DSC–MRI radiogenomics in gliomas hold the potential to provide increased predictive performance from models that generalize well and provide understandable patterns between IDH mutation status and the extracted features toward enabling the clinical translation of radiogenomics in neuro-oncology.

scholarly journals IDH Mutations Are Associated with an Increased Risk of Coronary Artery Disease and Cardiotoxicity in Patients with Established AML

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Badder Kattih ◽  
Amir Shirvani ◽  
Piroska Klement ◽  
Abel Martin Garrido ◽  
Razif Gabdoulline ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Board Of Directors ◽  
Research Funding ◽  
Idh Mutation ◽  
Advisory Committees ◽  
Mutation Status ◽  
Increased Risk ◽  
Idh Mutations ◽  
Artery Disease

Introduction: Clonal hematopoiesis initiated by acquired somatic mutations in hematopoietic cells has been identified as an independent driver of increased all-cause mortality, risk of coronary artery disease and heart failure. Oncogenic mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) lead to conversion of αKG to R-2-hydroxyglutarate (R-2HG), which is a competitive inhibitor of TET2 and a known oncometabolite. Oncometabolite R-2HG (produced by IDH mutant cells) has been implicated in pathological cardiac remodeling and dysfunction in preclinical studies. Whether IDH mutant leukemic cells in patients with established AML are also associated with the development of cardiovascular diseases or exacerbate cardiotoxicity during anthracycline containing chemotherapy is still unknown. Methods: In this observational study, a propensity score-based analysis was performed in 363 adult AML patients being stratified by mutation status in the IDH gene. To analyze whether the IDH mutation status in AML patients was associated with increased cardiotoxicity, we analyzed echocardiographic left ventricular ejection fraction (LVEF) in the control group (AML patients without IDH mutation) and the exposed group (AML patients with IDH mutation) at baseline and at different time points during AML therapy. Results: IDH 1 and IDH2 mutations occurred in 26 (7.2%) and 39 adult AML patients (10.7%), respectively. The median age of the total population was 60 years. The estimated 2-year relapse-free survival and overall survival rates in the overall study cohort were 49.4% (5-year RFS 38.9%) and 59.2% (5-year OS 43.1%) during a median follow-up of 7.6 years. IDH1 mutant AML patients exhibited a significantly higher prevalence of coronary artery disease (26.1% vs. 6.4%, p=0.002). A propensity score analysis by inverse probability-weighting was performed based on the 295 patients who received intensive cytarabine and anthracycline-containing chemotherapy. This analysis revealed an increased risk for a declining cardiac function during AML treatment in IDH1/2 mutated compared to IDH1/2 wild type patients [LVEF pretreatment compared to 10 months after diagnosis: 59.2% to 41.9% (P&lt;0.001) vs 58.5% to 55.4% (P=0.27), respectively], suggesting that the IDH mutations in AML patients were associated with a declining cardiac function during AML therapy, which was independent of measured baseline characteristics. To validate whether the oncometabolite R-2HG drives vulnerability of cardiac cells in patients with IDH mutant AML, human iPS-derived cardiomyocytes were exposed to R-2HG (or control) during anthracycline treatment. Indeed, an exaggerated sarcomere disarray when R-2HG was added to anthracycline treatment was identified by immunostaining in human induced pluripotent stem cell (hIPS) derived cardiomyocytes. By RNA sequencing of R-2HG exposed hiPS-derived cardiomyocytes during anthracycline treatment, we demonstrate the transcriptomic basis for putative biological processes mediating the increased cardiotoxicity. Conclusion: The presence of an IDH mutation in adult AML was associated with a higher prevalence of coronary artery disease and an exacerbated cardiotoxicity during anthracycline treatment, which was at least in part mediated by the oncometabolite R-2HG. Disclosures Thol: Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ganser:Novartis: Consultancy; Celgene: Consultancy. Heuser:BerGenBio ASA: Research Funding; Roche: Research Funding; Astellas: Research Funding; Janssen: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; PriME Oncology: Honoraria; Daiichi Sankyo: Consultancy, Research Funding; Stemline Therapeutics: Consultancy; Bayer: Consultancy, Research Funding; Karyopharm: Research Funding.

scholarly journals Noninvasive assessment of isocitrate dehydrogenase mutation status in cerebral gliomas by magnetic resonance spectroscopy in a clinical setting

2018 ◽  
Vol 128 (2) ◽  
pp. 391-398 ◽  
Author(s):  
Anna Tietze ◽  
Changho Choi ◽  
Bruce Mickey ◽  
Elizabeth A. Maher ◽  
Benedicte Parm Ulhøi ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Isocitrate Dehydrogenase ◽  
Prognostic Significance ◽  
Resonance Spectroscopy ◽  
Idh Mutation ◽  
Imaging Protocol ◽  
Mutation Status ◽  
Idh Mutations ◽  
Cerebral Gliomas

OBJECTIVEMutations in the isocitrate dehydrogenase (IDH) genes are of proven diagnostic and prognostic significance for cerebral gliomas. The objective of this study was to evaluate the clinical feasibility of using a recently described method for determining IDH mutation status by using magnetic resonance spectroscopy (MRS) to detect the presence of 2-hydroxyglutarate (2HG), the metabolic product of the mutant IDH enzyme.METHODSBy extending imaging time by 6 minutes, the authors were able to include a point-resolved spectroscopy (PRESS) MRS sequence in their routine glioma imaging protocol. In 30 of 35 patients for whom this revised protocol was used the lesions were subsequently diagnosed histologically as gliomas. Of the remaining 5 patients, 1 had a gangliocytoma, 1 had a primary CNS lymphoma, and 3 had nonneoplastic lesions. Immunohistochemistry and/or polymerase chain reaction were used to detect the presence of IDH mutations in the glioma tissue resected.RESULTSIn vivo MRS for 2HG correctly identified the IDH mutational status in 88.6% of patients. The sensitivity and specificity was 89.5% and 81.3%, respectively, when using 2 mM 2HG as threshold to discriminate IDH-mutated from wildtype tumors. Two glioblastomas that had elevated 2HG levels did not have detectable IDH mutations, and in 2 IDH-mutated gliomas 2HG was not reliably detectable.CONCLUSIONSThe noninvasive determination of the IDH mutation status of a presumed glioma by means of MRS may be incorporated into a routine diagnostic imaging protocol and can be used to obtain additional information for patient care.

Use of 2HG Levels in the Serum, Urine, or Bone Marrow to Predict IDH Mutations in Adults with Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2597-2597 ◽  
Author(s):  
Andrew M. Brunner ◽  
Donna S Neuberg ◽  
Seth A. Wander ◽  
Hossein Sadrzadeh ◽  
Karen K. Ballen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Predictive Value ◽  
Research Funding ◽  
Idh Mutation ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Mutation Status ◽  
Non Invasive ◽  
Idh Mutations

Abstract Mutations in genes encoding the isocitrate dehydrogenase 1/2 (IDH 1/2) enzymes increase production of the oncometabolite 2-hydroxyglutarate (2HG), resulting in elevated 2HG in patients with IDH-mutant AML. This may allow for non-invasive diagnostic and predictive markers of disease; however, the optimal threshold of 2HG levels to predict IDH mutation status, or whether 2-HG measurements in different compartments are equally predictive, is unknown. We measured 2-HG levels in serum, urine, bone marrow aspirate, and bone marrow cell pellet to determine the optimal predictive value of 2HG levels for IDH mutations at AML diagnosis. Patients with newly diagnosed AML had prospective measurements of 2HG levels at diagnosis by liquid chromatography-tandem mass spectrometry in serum, urine, marrow aspirate, and marrow pellet samples. Patients analyzed had IDH1 R132 and IDH2 R140 and R172 testing. Hotspot mutational profiling was performed for AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, KIT, KRAS, MAP2K1, NOTCH1, NRAS, PIK3CA, P53, and PTEN; patients were also tested for FLT3, NPM1, and CEBPA mutations. IDH1/2 mutant patients were compared to wildtype (WT) patients using a Wilcoxon rank sum, Fisher's exact, or Kruskal Wallis test, as appropriate. Performance characteristics of 2HG to predict the presence of IDH1/2 mutations were done using a recursive partitioning algorithm in R version 3.2.1, with the rpart package. 228 patients with newly diagnosed AML had 2HG levels in serum, urine, marrow aspirate, and marrow pellet samples. All patients had testing for IDH1 R132 and IDH2 R140 and R172 mutations. The patients were 56% male; 13 patients had APL, none with IDH mutations. IDH mutations were identified in 23% (n=52) of the cohort: IDH1 R132C (n=12), IDH2 R172 (n=9), and IDH2 R140Q (n=29), and 2 additional patients had mutations in both IDH1 R132 and IDH2 R140 (Table 1). The optimal test cut-off of 2HG to predict IDH status was 534.5 ng/mL in the serum (n=221), 16650 ng/mL in the urine (n=213), 2210 ng/mL in the marrow aspirate (n=190), and 1146 ng/2*10^6 cells in the pellet (n=159). Serum and pellet values had the greatest specificity for the presence of an IDH1/2 mutation (0.9882 and 1.000, respectively; Table 2). The positive predictive value of an elevated serum or pellet 2HG level at these cut-offs was 95.4% and 100%, given a 23% IDH mutation prevalence in this study population. The marrow aspirate had the greatest sensitivity (0.8837) and negative predictive value (96.6%). Urine 2HG levels were less sensitive than serum 2HG levels, although above the urine cut-off the specificity for IDH mutations was similar (Figure 1). 2HG levels in the serum, urine, and marrow can be used to identify IDH mutations in AML. Serum 2HG testing is an effective non-invasive mechanism to predict IDH1/2 mutation status. A serum cut-off of 534.5 ng/mL has a specificity of 0.9882 and, with an IDH mutation prevalence of 23%, was associated with a PPV of 0.9535.Table 1.Patient CharacteristicsNo IDH mutationIDH mutationTotalp-valueMale sex101 (57%)26 (50%)127 (56%)0.43Cytogenetics0.0002Favorable26 (15%)026 (12%)Intermediate95 (54%)41 (82%)136 (61%)Adverse52 (30%)9 (18%)61 (27%)Age (median, range)66 (20, 87)66.5 (41, 86)66 (20, 87)0.27WBC (median, range)5.35 (0.60, 315.4)3.65 (0.20, 333.2)5.25 (0.20, 333.2)0.33No IDH mutationIDH mutationNumber assessedp-valueNRAS27 (17%)9 (19%)2100.83KRAS16 (10%)0 (0%)2100.03TP5315 (9%)1 (2%)2100.13KIT2 (1%)1 (2%)2100.54FLT3ITD34 (20%)4 (8%)2180.06FLT3TKD10 (6%)2(4%)2180.74NPM129 (17%)15 (30%)2190.07CEBPA13 (13%)3 (10%)1021.002HG MeasurementsNo IDH mutationIDH mutationTotalSerum (ng/mL)79.5 [52,123] n=1701420 [675,2735] n=51101 [58,101] n=221Urine (ng/mL)3590 [2230,6220] n=16318300 [7260,59500] n=504330 [2450,8580] n=213Marrow aspirate (ng/mL)BQL [BQL,BQL] n=14718400 [4270,43100] n=43BQL [BQL,1430] n=190Pellet (1000 ng/2*10^6 cells)64 [BQL,169] n=1271420 [675,2735] N=32107 [BQL,500] n=159 Table 2. Test characteristics based on optimal 2HG cut-off, by compartment. Compartment 2HG cut-off Sensitivity Specificity 23% prevalence PPV NPV Serum 534.5 ng/mL 0.8039 0.9882 0.9535 0.9438 Urine 16650 ng/mL 0.5600 0.9877 0.9333 0.8798 Marrow Aspirate 2210 ng/mL 0.8837 0.9660 0.8837 0.9660 Marrow Pellet 1146 ng/2*10^6 cells 0.7813 1.000 1.000 0.9478 Figure 1. Relative frequencies of 2-HG levels according to cut-off values in serum (top) urine (bottom). Figure 1. Relative frequencies of 2-HG levels according to cut-off values in serum (top) urine (bottom). Figure 2. Figure 2. Disclosures Chen: Bayer: Consultancy, Research Funding. Stone:Agios: Consultancy; Celator: Consultancy; Pfizer: Consultancy; Merck: Consultancy; AROG: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Roche/Genetech: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Juno: Consultancy; Novartis: Research Funding. Fathi:Exelexis: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy; Takeda Pharmaceuticals International Co.: Research Funding.

scholarly journals INNV-04. IDH MUTATION PREDICTION IN GLIOMA: A MULTIMODAL APPROACH

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi131-vi131
Author(s):  
Tareq Juratli ◽  
Amir Zolal ◽  
Sebastian Stasik ◽  
Mirko Pietzsch ◽  
Graeme Eisenhofer ◽  
...  
Keyword(s):  
Mutant Cell ◽  
Diagnostic Techniques ◽  
Small Subset ◽  
Idh Mutation ◽  
Newly Diagnosed ◽  
Mutation Status ◽  
Single Voxel ◽  
Idh Mutations ◽  
Liquid Chromatography Tandem Mass ◽  
Mutation Prediction

Abstract OBJECTIVE Non-invasive and accurate diagnostic techniques to detect isocitrate dehydrogenase (IDH) mutant glioma may have great potential in routine clinical practice. With this in mind, we performed a multimodal diagnostic approach to predict the IDH mutation status in newly diagnosed gliomas using: 2-Hydroxyglutarate (2HG) single-voxel spectroscopy (SVS), IDH-mutant cell-free tumor-derived DNA (tDNA) in the CSF, in addition to 2HG (D- and L- forms) concentration measurement in the CSF. METHODS 2HG MR spectroscopy was obtained in 18 patients with a newly diagnosed IDH-mutant glioma. The IDH1/2 mutation status was determined using next generation sequencing in the glioma tissue and in the CSF-tDNA (n=55). In addition, in a subset of patients (n=15), 2HG concentrations were measured in the CSF using liquid chromatography-tandem mass spectrometry (LCMS). Ratios of D-and L-2HG were used to evaluate differences in 2HG accumulation in tumors. RESULTS IDH mutations were correctly predicted using the 2HG spectroscopy with 93.3% sensitivity (17/18, 95% CI, 85.3–100%) and 100% specificity (18/18, 95% CI, 88.6–100%). The IDH mutation in the CSF-tDNA was successfully detected with 100% specificity (95% CI, 87.6–100%) and 73.3% sensitivity (95% CI, 65.6–88.3%). The range of the IDH mutation variant allele frequency (VAF) in the CSF-tDNA was 1.53- 47.9%. 2HG detection in the CSF revealed higher sensitivity (100%) and specificity (100%) in a small subset of patients (n = 7). The D-2HG/L-2HG ratios in IDH-mutant cases varied between 1.2 – 13.8, compared with 0.1 – 0.5 in IDH wild-type gliomas. CONCLUSION Our findings suggest that 2HG spectroscopy and 2HG detection in the CSF are two reliable methods in IDH mutation prediction in gliomas. On the other hand, the sensitivity of genomic IDH mutation detection in the CSF-tDNA was lower when compared with 2HG detection. Further studies are needed to complement the findings of our exploratory analysis.

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