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.T he microscopic review of tissue biopsies frequently remains the sole source of intraoperative diagnostic information, and many important surgical decisions such as the extent of tumor resection are based on this information. This approach is timeconsuming, requiring nearly 30 min between the moment a tissue is biopsied and the time the pathologist's interpretation is communicated back to the surgeon. Even after the report of the final pathologic diagnosis is issued days later, a lot of diagnostic, prognostic, and predictive information is left undiscovered and unexamined within the tissue. Tools that provide more immediate feedback to the surgeon and the pathologist and that also rapidly extract detailed molecular information could transform the management of care for cancer patients.MS offers the possibility for the in-depth analysis of the proteins and lipids that comprise tissues (1, 2). We have recently shown that desorption electrospray ionization (DESI) MS is a powerful methodology for characterizing lipids within tumor specimens (3-6). The intensity profile of lipids ionized from within tumors can be used for classifying tumors and for providing valuable prognostic information such as tumor subtype and grade. Because DESI MS is performed in ambient conditions with minimal pretreatment of the samples (7,8), there is the potential to provide diagnostic information rapidly within the operating room (4, 6, 9). The ability to quickly acquire such valuable diagnostic information from lipids prompted us to determine whether we could use DESI MS to detect additional molecules of diagnostic value within tumors, such as their metabolites.Recently,...

Lipid and metabolite profiles of human brain tumors by desorption electrospray ionization-MS

“…2HG is a downstream metabolite of IDH mutations and serves as an important prognostic indicator (32,33). The presence of m/z 147 in specimen 51 was confirmed by MS/MS (SI Appendix, Fig.…”

“…To date, DESI-MS analysis of tissue and cytological smears has been only briefly explored (7,33). Smears are commonly performed by placing a minute amount of tissue onto a glass slide and then physically spreading the material to achieve a relatively uniform and diffuse layer of cellular material for staining and subsequent pathology.…”

“…The presence of m/z 147 in the metabolite profile (full-scan mode) was indicative of 2HG presence, but additional specificity and confirmation were achieved by MS/MS. The detection of 2HG and its correlation with IDH mutation status are outside the scope of this report, having been investigated previously (33). The ability to ascertain such information rapidly expands the value of DESI-MS methodology beyond tissue diagnosis.…”

Cross-reactivity of the BRAF VE1 antibody with epitopes in axonemal dyneins leads to staining of cilia

“…[5][6][7] The use of these antibodies is particularly important as the results of genetic testing can still take weeks to report in many institutions. 8 As these antibodies are so commonly used, it is important to have a thorough understanding of their limitations so as to avoid incorrect interpretations.…”

Skin molecule maps using mass spectrometry

“…Spatial and chemical information coregistration allows MS data to be used to answer questions like, "is this area cancerous?" The recognition of the diagnostic role of lipids is a recent phenomenon, but lipid MS now provides tools for improved tumor surgery via molecular detection of cancer margins (13,14) and discovery of new endogenous and onco-metabolite markers (15). Ambient MS techniques fit well in the surging effort to gain chemical information on complex biological systems and, in future, one can visualize use of portable MS/MS instruments.…”