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Jul 18, 2016 - an Integral Technology in the Operating Room of the Future? ... laboratory at Purdue University described the use of an emerging ... thology and Immunology and 3 Surgery, Baylor College of Medicine, Houston, TX. * Address ...

Papers in Press. Published July 18, 2016 as doi:10.1373/clinchem.2016.258723 The latest version is at http://hwmaint.clinchem.org/cgi/doi/10.1373/clinchem.2016.258723 Clinical Chemistry 62:9 000 – 000 (2016)

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Will Ambient Ionization Mass Spectrometry Become an Integral Technology in the Operating Room of the Future? Jialing Zhang,1 Wendong Yu,2 James Suliburk,3 and Livia S. Eberlin1*

Cancer surgeons face on a daily basis the difficult task of determining the delicate boundary between cancerous and normal tissue. Additionally, they must decide how much noncancerous margin of normal tissue to resect along with the tumor. Among the factors considered when deciding the extent of tissue resection are tumor type, location next to vital structures, morbidity of aggressive resection, tumor aggressiveness, adjunct chemotherapies available, survival rates and the patients’ medical background. In the majority of cancer surgeries, the resected tissue samples are sent to a nearby room, often called the “frozen room,” for tissue processing and evaluation. The tissue is quickly frozen, sectioned, stained and interrogated using light microscopy by an expert pathologist who carefully evaluates if the surgical margins contain cancer cells (positive margin) or not (negative margin). This process of intraoperative surgical margin evaluation has been performed in clinical practice for decades, although it has many challenges. Freezing artifacts occur during tissue processing and interfere with tissue structure and cell morphology, thus complicating pathologic interpretation. Moreover, certain tumor cells are very difficult to recognize due to their atypical pattern of growth and shape. Often more than one pathologist is involved to make a final and difficult decision on margin status. Logistically, in most hospitals in the US, the frozen room serves several operating rooms (ORs),4 and depending on the workload, a surgeon may need to wait an undesirable amount of time (over 30 min) for a final reading before deciding whether to conclude or continue a surgery. This process results in prolonged length of surgery and associated increase in anesthesia time, increasing the risk of surgical site infection and physiologic stress to the patient.

1

Department of Chemistry, University of Texas at Austin, Austin, TX; Departments of 2 Pathology and Immunology and 3 Surgery, Baylor College of Medicine, Houston, TX. * Address correspondence to this author at: The University of Texas at Austin, 105 East 24th St., Stop A5300, Austin, TX, 78712. E-mail [email protected] Received April 5, 2016; accepted June 16, 2016. Previously published online at DOI: 10.1373/clinchem.2016.258723 © 2016 American Association for Clinical Chemistry 4 Nonstandard abbreviations: OR, operating room; DESI-MS, desorption electrospray ionization mass spectrometry; NAA, N-acetyl-aspartic acid.

In brain cancer surgery, surgical margin evaluation is critical because sparing normal marginal tissue may significantly impact postoperative quality of life. New technologies that provide accurate and rapid diagnosis of surgical margins could improve surgical practice and treatment outcome. A recent publication in the Proceedings of the National Academy of Sciences (1 ) from Cooks’ laboratory at Purdue University described the use of an emerging technology, desorption electrospray ionization mass spectrometry (DESI-MS), to analyze the lipid and metabolite profiles of human brain tumors with the perspective of using this technique intraoperatively for tumor margin evaluation. DESI-MS is one of a group of ambient ionization techniques in MS that allow samples to be directly analyzed for their chemical composition without the need for extensive sample preprocessing and without chromatographic separation. The experiment is performed in open air, commonly on tissue sections, and could yield diagnostic information in about 1 min. Using banked tissue samples (n ⫽ 58), the authors investigated the molecular composition of gliomas, meningiomas, pituitary tumors, and normal brain white matter and grey matter. Data using optimized conditions in the negative ion mode separately analyzed the metabolite (m/z 80 – 200) and the lipid (m/z 200 –1000) regions of the mass spectra. Highly reproducible and characteristic lipid mass spectra were observed for the white and the grey matter regions of normal brain tissues yet, differences in lipid abundances enabled distinction between various anatomical regions of the brain. The lipid profiles from normal brain tissues were clearly distinct from glioma tissues, and consistently showed an increased abundance of the lipids, glycerophosphocholine (PC 34:1) and glycerophosphoinositol (PI 38:4). Principal component analysis of the lipid data showed dispersion within the glioma class, which the authors associated with infiltration of tumor cells into normal tissue, as well as the presence of various glioma subtypes that have been previously shown to have different lipid profiles (2 ). However, reliable differentiation was not possible when the tissue presented low levels of infiltration, including regions containing ⬍25% tumor cell concentration. Interestingly, when exploring metabolic profiles, N-acetyl-aspartic acid (NAA), detected at m/z 174, was found to enable clear discrimi1

Copyright (C) 2016 by The American Association for Clinical Chemistry

Perspectives nation of normal brain from gliomas. This finding supports previous magnetic resonance imaging studies that indicated the significance of NAA in discriminating normal and diseased neural tissues. This was the first study to describe the detection of the oncometabolite NAA in brain tissue by MS. In addition to NAA, the authors concomitantly detected the oncometabolite 2-hydroxyglurate (m/z 147), previously reported as a marker of isocitrate dehydrogenase (NADP(⫹)) 1, cytosolic (IDH1) mutation and therefore, an important prognostic indicator (3 ). When combining metabolite and lipid information using statistical analysis, the method was particularly powerful for estimating tumor cell concentration within tissue samples, which is of immense value in predicting diffuse and infiltrative brain tumors during surgical resection. Remarkably, fused lipid and metabolite data were subjected to principal component analysis and enabled separation of gliomas, meningiomas and pituitary tumors with little ambiguity suggesting that an unknown sample from one of these three types of tumor could be chemically recognized solely based on the DESI-MS profiles. Further clinical relevance was shown through the analysis of tissue smears. These samples, prepared from the frozen tissue analyzed using a 3D-imprinted device, yielded absolute MS signal equal to that of tissue sections. More importantly, the patterns of the ions were highly similar to those obtained from tissue sections. These exciting results suggest that the same predictive models built from frozen tissue sections could be used to analyze and obtain diagnostic information from tissue smears in a high throughput manner. This manuscript is one in a series of similar reports by the Cooks group and other researchers who are striving to fully develop and validate ambient ionization MS technology for clinical use. For a detailed review of the use of ambient ionization MS for cancer diagnosis and surgical margin evaluation, please see reference (4 ). DESI-MS and similar ambient ionization MS techniques have been used previously to investigate the lipid and metabolic profiles of a variety of human cancers including gastric, breast, brain, intestinal, prostate and others. Few studies have applied this methodology to prospectively collected clinical samples including surgical margins. Ambient ionization MS has also been tested intraoperatively for real time analysis of tissue biopsies and for in vivo tissue analysis. At the Brigham and Women’s Hospital at Harvard Medical School for example, a mass spectrometer coupled to a DESI source is currently being used in the surgical suite to acquire data from resected brain tissue (3 ). At the Imperial College London Department of Surgery and Cancer, an electrosurgical device integrated to an MS system is being used to analyze tissue in vivo during surgery (5 ). The Cooks group is presently testing the methods described intrasurgically for brain 2

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cancer surgical margin evaluation using tissue smears at the Indiana University School of Medicine. Yet, apart from these small research-based investigations, is it realistic to expect ambient ionization MS to be an integral technology in the OR? Many efforts are underway to integrate a wide range of technologies in the OR of the future. Magnetic resonance imaging, positron emission tomography, Raman spectroscopy, fluorescent imaging and optical coherence tomography are a few of the many technologies that are currently being tested in ORs with the goal of adding diagnostic information and providing real time surgical margin evaluation. Careful evaluation of the long-term benefits to patients of the use of new technologies is needed to determine their value in clinical practice. Since present-day ORs tend to be inefficient and overcrowded, with turnover between cases lengthy and variable, new technologies and devices should be introduced without complicating an already complex environment. Improved integration of technology along with enhanced communication will be needed to successfully test and implement new tools. For example, the ongoing migration from traditional surgical procedures to minimally invasive, robotic and image-guided surgeries calls for new technologies to be automated and minimally destructive. Integrating ambient ionization MS tools to laparoscopic-based technologies and other robotic devices is a likely path for its inclusion into the surgical workflow. Availability of validated databases and automated computational methods for real time output of predictive results using advanced statistical tools is key for acceptance of ambient ionization MS by medical professionals. Smaller and cheaper mass spectrometers with enough performance for molecular discrimination would also be more easily accepted in the clinical space. Because ambient ionization MS provides great analytical sensitivity, specificity, and an immense depth and richness of molecular information in real time, directly from tissue samples, the prospect of using this technology in and outside of the OR is broad and very exciting. We foresee real time preoperative diagnosis of biofluids and biopsy samples as a promising application yet to be more carefully explored using ambient ionization MS, and our group and others are working toward this goal. Correlation between metabolic/lipid information and molecular subtypes or gene expression could provide increased molecular information that may improve cancer diagnosis and treatment. Diseases other than cancer for which more accurate and rapid diagnosis are needed would also benefit from this rapid and powerful technique. As with any other technology, the road ahead to translation to clinics is challenging. Further refinement of the techniques as well as large multicenter research studies is needed to validate the results and properly evaluate its benefits to patients. Nonetheless, the steep increase in the number of studies successfully using ambient ionization

Ambient Ionization Mass Spectrometry in the Operating Room

MS for clinical diagnosis indicates that we should expect lipid and metabolite information to be included in clinical practice in the next couple of decades.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

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Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: Employment or Leadership: None declared. Consultant or Advisory Role: None declared. Stock Ownership: None declared. Honoraria: None declared. Research Funding: None declared. Expert Testimony: None declared. Patents: None declared.

References 1. Jarmusch AK, Pirro V, Baird Z, Hattab EM, Cohen-Gadol AA, Cooks RG. Lipid and metabolite profiles of human brain tumors by desorption electrospray ionization-ms. Proc Natl Acad Sci USA 2016;113:1486 –91. 2. Eberlin LS, Norton I, Orringer D, Dunn IF, Liu XH, Ide JL, et al. Ambient mass spectrometry for the intraoperative

molecular diagnosis of human brain tumors. Proc Natl Acad Sci USA 2013;110:1611– 6. 3. Santagata S, Eberlin LS, Norton I, Calligaris D, Feldman DR, Ide JL, et al. Intraoperative mass spectrometry mapping of an onco-metabolite to guide brain tumor surgery. Proc Natl Acad Sci USA 2014;111: 11121– 6.

4. Ifa DR, Eberlin LS. Ambient ionization mass spectrometry for cancer diagnosis and surgical margin evaluation. Clin Chem 2016;62:111–23. 5. Balog J, Sasi-Szabo L, Kinross J, Lewis MR, Muirhead LJ, Veselkov K, et al. Intraoperative tissue identification using rapid evaporative ionization mass spectrometry. Sci Transl Med 2013;5.

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