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Ambient Mass Spectrometry for the Intraoperative Molecular Diagnosis of Human Brain Tumors

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Ambient Mass Spectrometry for the Intraoperative Molecular Diagnosis of Human Brain Tumors Ambient mass spectrometry for the intraoperative molecular diagnosis of human brain tumors Livia S. Eberlina, Isaiah Nortonb, Daniel Orringerb, Ian F. Dunnb, Xiaohui Liub, Jennifer L. Ideb, Alan K. Jarmuscha, Keith L. Ligonc, Ferenc A. Joleszd, Alexandra J. Golbyb,d, Sandro Santagatac, Nathalie Y. R. Agarb,d,1, and R. Graham Cooksa,1 aDepartment of Chemistry and Center for Analytical Instrumentation Development, Purdue University, West Lafayette, IN 47907; and Departments of bNeurosurgery, cPathology, and dRadiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 Edited by Jack Halpern, The University of Chicago, Chicago, IL, and approved December 5, 2012 (received for review September 11, 2012) The main goal of brain tumor surgery is to maximize tumor resection at Brigham and Women’s Hospital (BWH), created an opportu- while preserving brain function. However, existing imaging and nity for collecting information about the extent of tumor resection surgical techniques do not offer the molecular information needed during surgery (5, 6). Although brain tumor resection typically to delineate tumor boundaries. We have developed a system to requires multiple hours, intraoperative MRI can be completed rapidly analyze and classify brain tumors based on lipid information and information evaluated within an hour. However, MRI has acquired by desorption electrospray ionization mass spectrometry limited ability to distinguish residual tumor from surrounding (DESI-MS). In this study, a classifier was built to discriminate gliomas normal brain (9). In consequence, there is a need for more de- and meningiomas based on 36 glioma and 19 meningioma samples. tailed molecular information to be acquired on a timescale closer The classifier was tested and results were validated for intraoper- to real time than can be supplied by MRI. ative use by analyzing and diagnosing tissue sections from 32 Standard histopathology methods are the gold standard for detecting the presence of tumor and can provide diagnostic in- surgical specimens obtained from five research subjects who un- formation during surgery within an hour, but are typically limited derwent brain tumor resection. The samples analyzed included to the evaluation of one or very few samples. The most useful oligodendroglioma, astrocytoma, and meningioma tumors of dif- ancillary tests in diagnostic pathology exploit changes in nucleic ferent histological grades and tumor cell concentrations. The acids that are at the foundation of tumors: DNA point mutations, CHEMISTRY molecular diagnosis derived from mass-spectrometry imaging cor- chromosomal translocations, changes in copy number, and most responded to histopathology diagnosis with very few exceptions. recently, the changes in mRNA levels (10). Beyond nucleic acids, Our work demonstrates that DESI-MS technology has the potential data on proteins and lipids in tissue can reveal important in- to identify the histology type of brain tumors. It provides in- formation about physiology and disease. Proteomic information is formation on glioma grade and, most importantly, may help define used regularly in pathology, albeit in a low-throughput manner tumor margins by measuring the tumor cell concentration in using immunohistochemistry. The lipid constituents of tissues, a specimen. Results for stereotactically registered samples were however, remain entirely unused in diagnostic practice as lip- correlated to preoperative MRI through neuronavigation, and idomic information has until recently been impractical to acquire. visualized over segmented 3D MRI tumor volume reconstruction. Now, desorption electrospray ionization mass spectrometry MEDICAL SCIENCES Our findings demonstrate the potential of ambient mass spectrom- (DESI-MS) (11), as well as related MS-imaging methods (12), etry to guide brain tumor surgery by providing rapid diagnosis, and offer the possibility of incorporating lipid information into tumor tumor margin assessment in near–real time. diagnostics. DESI is one of a recently developed group of ioni- zation techniques in MS in which samples are examined in the – urgery is a key component in the treatment of brain tumors. ambient environment with minimal pretreatment (13 17). Using SSubstantial evidence suggests that a smaller volume of post- DESI, direct lipid analysis from biological samples such as tissue operative residual tumor is associated with an improved prog- sections can be performed rapidly and routinely. This micro- nosis (1–4). One of the greatest barriers to achieving optimal extraction experiment takes less than a second and gives a large amount of information on an individual small spot (pixel) on the surgical results in infiltrative tumors is the difficulty in dis- unmodified tissue. Samples can be examined also by scanning tinguishing tumor from normal brain (5–7). Failure to discern them in 2D space while a spray of charged droplets impinges on where the border of the lesion ends and viable, minimally infil- the tissue, extracting lipids into secondary microdroplets that are trated brain begins increases the likelihood of inadequate re- continuously transferred to a mass spectrometer. Chemical in- section and neurological damage. Although maximal surgical formation obtained from such scans is then represented in the resection with the goal of gross total tumor resection is desirable, form of 2D images recording relative abundances and spatial in practice, delineation of resection margins is difficult because fi fi distributions of speci c ions. In a single experiment, DESI-MS tumors can closely resemble healthy brain, often in ltrate brain allows the characterization and imaging of many lipids including tissue, and may be immediately adjacent to critical functional brain fatty acyls, glycerophospholipids, glycerolipids, and sphingolipids tissue. Aggressive resection can increase the risk for postoperative fi (18). DESI-MS imaging of tissue sections from banked tissue has neurological de cits (7). For example, brain tumors located near been shown to enable disease diagnosis based on lipid profiles of critical brain areas subserving primary motor, sensory, or language different human diseases, such as bladder (19), kidney (20), functions are difficult to resect maximally while avoiding post- operative neurological deficits (8). Therefore, the principal chal- lenge and objective of neurosurgical intervention is to maximize Author contributions: L.S.E., I.N., F.A.J., A.J.G., N.Y.R.A., and R.G.C. designed research; the resection of tumor, and minimize the potential for neurological L.S.E., I.N., D.O., I.F.D., A.K.J., and S.S. performed research; X.L., J.L.I., and K.L.L. contributed deficit by preserving critical tissue. Intraoperatively acquired new reagents/analytic tools; L.S.E., I.N., S.S., N.Y.R.A., and R.G.C. analyzed data; D.O., I.F.D., images can provide the neurosurgeon with the information needed and A.J.G. performed the surgery; and L.S.E., N.Y.R.A., and R.G.C. wrote the paper. to perform real-time, image-guided surgery. The authors declare no conflict of interest. A variety of mapping techniques have been developed to pro- This article is a PNAS Direct Submission. vide the surgeon with an understanding of the relationship of the 1To whom correspondence may be addressed. E-mail: [email protected], nagar@bwh. tumor to surrounding key cortical areas, but none offers the harvard.edu, or [email protected]. molecular precision required to delineate tumor boundaries and This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. evaluate the extent of infiltration. Intraoperative MRI, developed 1073/pnas.1215687110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1215687110 PNAS Early Edition | 1of6 Downloaded by guest on September 23, 2021 prostate (21), and brain cancer (22, 23). These studies demon- complications. A small subset of meningiomas is more aggres- strate the potential value of DESI in providing tissue diagnosis in sive, and also requires surgical intervention. In contrast to glio- a few seconds for intraoperative use, a task also being investigated mas, meningiomas usually feature a very clear border between by related mass-spectrometry methods (24). tumor and normal brain. The World Health Organisation (WHO) recognizes over 125 Using a set of banked tumor samples, we have previously types of brain tumors according to histopathological evaluation. demonstrated that gliomas of different subtypes (oligoden- Tissue is differentiated according to cellular composition, in- drogliomas, astrocytomas, and oligoastrocytomas), grades and cluding characteristics of astrocytic, ependymal, meningeal, neu- cell concentrations (a marker of tumor infiltration into normal ronal, oligodendrocytic cells, and according to tumor origin. The tissue) could be rapidly classified by DESI-MS imaging using WHO classification system also grades malignancy according to multivariate statistical analysis and machine learning (23). In the such characteristics as proliferation, cellular and nuclear mor- present study, we expanded our classification strategy for brain phology, necrosis, and the presence of abnormal vasculature cancers by incorporating meningioma as a tumor type. The more (25). Glial tumors, gliomas, account for 30% of all intracranial comprehensive classification system is tested and validated tumors (26). The main subtypes are astrocytoma and oligoden- through application to the diagnosis and tumor margin assess- droglioma, of which about 70% are grade III or higher. Grades
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