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Intraoperative mass spectrometry mapping of an onco-metabolite to guide brain tumor surgery.

ABSTRACT: For many intraoperative decisions surgeons depend on frozen section pathology, a technique developed over 150 y ago. Technical innovations that permit rapid molecular characterization of tissue samples at the time of surgery are needed. Here, using desorption electrospray ionization (DESI) MS, we rapidly detect the tumor metabolite 2-hydroxyglutarate (2-HG) from tissue sections of surgically resected gliomas, under ambient conditions and without complex or time-consuming preparation. With DESI MS, we identify isocitrate dehydrogenase 1-mutant tumors with both high sensitivity and specificity within minutes, immediately providing critical diagnostic, prognostic, and predictive information. Imaging tissue sections with DESI MS shows that the 2-HG signal overlaps with areas of tumor and that 2-HG levels correlate with tumor content, thereby indicating tumor margins. Mapping the 2-HG signal onto 3D MRI reconstructions of tumors allows the integration of molecular and radiologic information for enhanced clinical decision making. We also validate the methodology and its deployment in the operating room: We have installed a mass spectrometer in our Advanced Multimodality Image Guided Operating (AMIGO) suite and demonstrate the molecular analysis of surgical tissue during brain surgery. This work indicates that metabolite-imaging MS could transform many aspects of surgical care.

SUBMITTER: Santagata S

PROVIDER: S-EPMC4121790 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Intraoperative mass spectrometry mapping of an onco-metabolite to guide brain tumor surgery.

Santagata Sandro S Eberlin Livia S LS Norton Isaiah I Calligaris David D Feldman Daniel R DR Ide Jennifer L JL Liu Xiaohui X Wiley Joshua S JS Vestal Matthew L ML Ramkissoon Shakti H SH Orringer Daniel A DA Gill Kristen K KK Dunn Ian F IF Dias-Santagata Dora D Ligon Keith L KL Jolesz Ferenc A FA Golby Alexandra J AJ Cooks R Graham RG Agar Nathalie Y R NY

Proceedings of the National Academy of Sciences of the United States of America 20140630 30

For many intraoperative decisions surgeons depend on frozen section pathology, a technique developed over 150 y ago. Technical innovations that permit rapid molecular characterization of tissue samples at the time of surgery are needed. Here, using desorption electrospray ionization (DESI) MS, we rapidly detect the tumor metabolite 2-hydroxyglutarate (2-HG) from tissue sections of surgically resected gliomas, under ambient conditions and without complex or time-consuming preparation. With DESI M ...[more]

PMID: 24982150

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Project description:Surgery remains the first and most important treatment modality for the majority of solid tumors. Across a range of brain tumor types and grades, postoperative residual tumor has a great impact on prognosis. The principal challenge and objective of neurosurgical intervention is therefore to maximize tumor resection while minimizing the potential for neurological deficit by preserving critical tissue.To introduce the integration of desorption electrospray ionization mass spectrometry into surgery for in vivo molecular tissue characterization and intraoperative definition of tumor boundaries without systemic injection of contrast agents.Using a frameless stereotactic sampling approach and by integrating a 3-dimensional navigation system with an ultrasonic surgical probe, we obtained image-registered surgical specimens. The samples were analyzed with ambient desorption/ionization mass spectrometry and validated against standard histopathology. This new approach will enable neurosurgeons to detect tumor infiltration of the normal brain intraoperatively with mass spectrometry and to obtain spatially resolved molecular tissue characterization without any exogenous agent and with high sensitivity and specificity.Proof of concept is presented in using mass spectrometry intraoperatively for real-time measurement of molecular structure and using that tissue characterization method to detect tumor boundaries. Multiple sampling sites within the tumor mass were defined for a patient with a recurrent left frontal oligodendroglioma, World Health Organization grade II with chromosome 1p/19q codeletion, and mass spectrometry data indicated a correlation between lipid constitution and tumor cell prevalence.The mass spectrometry measurements reflect a complex molecular structure and are integrated with frameless stereotaxy and imaging, providing 3-dimensional molecular imaging without systemic injection of any agents, which can be implemented for surgical margins delineation of any organ and with a rapidity that allows real-time analysis.

Project description:BackgroundSurgical 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.MethodsA 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.ResultsAssessment 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).ConclusionsThe 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.

Project description:Mass spectrometry (MS) is a sensitive, specific and versatile analytical technique in the clinical laboratory that has recently undergone rapid development. From initial use in metabolic profiling, it has matured into applications including clinical toxicology assays, target hormone and metabolite quantitation, and more recently, rapid microbial identification and antimicrobial resistance detection by matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). In this mini-review, we first succinctly outline the basics of clinical mass spectrometry. Examples of hard ionization (electron ionization) and soft ionization (electrospray ionization, MALDI) are presented to demonstrate their clinical applications. Next, a conceptual discourse on mass selection and determination is presented: quadrupole mass filter, time-of-flight mass spectrometer and the Orbitrap; and MS/MS (tandem-in-space, tandem-in-time and data acquisition), illustrated with clinical examples. Current applications in (1) bacterial and fungal identification, antimicrobial susceptibility testing and phylogenetic classification, (2) general unknown urine toxicology screening and expanded new-born metabolic screening and (3) clinical metabolic profiling by gas chromatography are outlined. Finally, major limitations of MS-based techniques, including the technical challenges of matrix effect and isobaric interference; and novel challenges in the post-genomic era, such as protein molecular variants, are critically discussed from the perspective of service laboratories. Computer technology and structural biology have played important roles in the maturation of this field. MS-based techniques have the potential to replace current analytical techniques, and existing expertise and instrument will undergo rapid evolution. Significant automation and adaptation to regulatory requirements are underway. Mass spectrometry is unleashing its potentials in clinical laboratories.

Dataset Information

Intraoperative mass spectrometry mapping of an onco-metabolite to guide brain tumor surgery.

Publications

Intraoperative mass spectrometry mapping of an onco-metabolite to guide brain tumor surgery.

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