Intraoperative Mass Spectrometry Platform for IDH Mutation Status Prediction, Glioma Diagnosis, and Estimation of Tumor Cell Infiltration

Abstract

Background Surgical tumor resection is the primary treatment option for diffuse glioma, the most common malignant brain cancer. The intraoperative diagnosis of gliomas from tumor core samples can be improved by use of molecular diagnostics. Further, residual tumor at surgical margins is a primary cause of tumor recurrence and malignant progression. This study evaluates a desorption electrospray ionization mass spectrometry (DESI-MS) system for intraoperative isocitrate dehydrogenase (IDH) mutation assessment, estimation of tumor cell infiltration as tumor cell percentage (TCP), and disease status. This information could be used to enhance the extent of safe resection and so potentially improve patient outcomes. Methods A mobile DESI-MS instrument was modified and used in neurosurgical operating rooms (ORs) on a cohort of 49 human subjects undergoing craniotomy with tumor resection for suspected diffuse glioma. Small tissue biopsies (ntotal = 203) from the tumor core and surgical margins were analyzed by DESI-MS in the OR and classified using univariate and multivariate statistical methods. Results Assessment of IDH mutation status using DESI-MS/MS to measure 2-hydroxyglutarate (2-HG) ion intensities from tumor cores yielded a sensitivity, specificity, and overall diagnostic accuracy of 89, 100, and 94%, respectively (ncore = 71). Assessment of TCP (categorized as low or high) in tumor margin and core biopsies using N-acetyl-aspartic acid (NAA) intensity provided a sensitivity, specificity, and accuracy of 91, 76, and 83%, respectively (ntotal = 203). TCP assessment using lipid profile deconvolution provided sensitivity, specificity, and accuracy of 76, 85, and 81%, respectively (ntotal = 203). Combining the experimental data and using PCA-LDA predictions of disease status, the sensitivity, specificity, and accuracy in predicting disease status are 63%, 83%, and 74%, respectively (ntotal = 203). Conclusions The DESI-MS system allowed for identification of IDH mutation status, glioma diagnosis, and estimation of tumor cell infiltration intraoperatively in a large human glioma cohort. This methodology should be further refined for clinical diagnostic applications.

Metabolomics for personalized medicine: the input of analytical chemistry from biomarker discovery to point-of-care tests

“…Although there are some liquid chromatography coupled to mass spectrometry systems that are CE-IVD (i.e., European directive for In Vitro Diagnostics) approved for clinical biochemistry, toxicology, or therapeutic drug monitoring, and mass spectrometers can be used in operating rooms [139,140], not all medical laboratories are and will be equipped with mass spectrometers (especially high-resolution instruments) and very few of them with nuclear magnetic resonance instruments. Thus, other analytical methods, such as enzyme assays, immunoassays, and biosensors, have to be envisaged for metabolite detection.…”

Cancer Surgery 2.0: Guidance by Real-Time Molecular Technologies

“…Spatial tissue analysis has been possible by the development of several imaging methodologies, for example, DESI-MSI, LAESI, and MALDESI. Out of many, DESI is the most used for chemical imaging and intraoperative diagnosis of tissue samples [101][102][103]. In the majority of analyzed clinical samples, lipid species encompassing different classes, such as fatty acids and glycerophospholipids, were observed as the discriminating molecules in cancer vs. normal tissue comparison.…”

Lipid Profiling in Cancer Diagnosis with Hand-Held Ambient Mass Spectrometry Probes: Addressing the Late-Stage Performance Concerns

“…The issue of spatial resolution (often not at single cell levels in prominent ambient MS methods) causes sensitivity of signal to tumour cellularity, as shown in a DESI-MS lipidomic profiling study of brain cancers [95] and the localization of high 2-hydroxyglutarate (2HG) signal levels in the regions of glioblastoma tumours with a dense cellularity [10]. While this sensitivity can be utilized to estimate tumour cell percentage [96], which is in its own right a useful clinical indicator currently only obtainable by time consuming histologic staining and microscopy, caution must be exercised in the interpretation of ambient MS profiles associated with residual disease presence. Residual HER2 expression within breast tumours [97] in a proteomic MALDI-MS study has been shown to influence receptor status predictions [98].…”