Mass spectrometry imaging as a tool for surgical decision‐making

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202

Distinguishing tumor from normal glandular breast tissue is an important step in breast-conserving surgery. Because this distinction can be challenging in the operative setting, up to 40% of patients require an additional operation when traditional approaches are used.Here, we present a proof-of-concept study to determine the feasibility of using desorption electrospray ionization mass spectrometry imaging (DESI-MSI) for identifying and differentiating tumor from normal breast tissue. We show that tumor margins can be identified using the spatial distributions and varying intensities of different lipids. Several fatty acids, including oleic acid, were more abundant in the cancerous tissue than in normal tissues. The cancer margins delineated by the molecular images from DESI-MSI were consistent with those margins obtained from histological staining. Our findings prove the feasibility of classifying cancerous and normal breast tissues using ambient ionization MSI. The results suggest that an MSbased method could be developed for the rapid intraoperative detection of residual cancer tissue during breast-conserving surgery.B reast cancer is the most commonly diagnosed carcinoma in women in the United States and Western countries. Breast conservation surgery (BCS) has become the preferred treatment option for many women with early-stage breast cancer (1). BCS entails resection of the tumor, with a clean margin of normal tissue around it. Surgery is usually followed by radiation therapy. Results from seven large randomized prospective studies, with the largest two having over 20 y of follow-up, have shown equal survival when comparing BCS coupled with whole-breast radiation and mastectomy (2, 3).Normally, breast surgeons aim to remove a patient's tumor, along with a rim of normal tissue that is free of cancer. Preoperative mammography, ultrasonography, or MRI may be used by the surgeon to guide adequate resection (4-6). Despite numerous improvements in imaging and surgical technique, the need for reexcision to achieve complete tumor resection in the United States typically ranges from 20-40% (7-15), and has been reported as being as high as 60% (16). The importance of reexcision is underscored by numerous studies, which have shown that incomplete resection of tumor and positive margins are associated with increased locoregional recurrence compared with negative margins (12,(17)(18)(19)(20). Furthermore, the landmark meta-analysis performed by the Early Breast Cancer Trialists' Collaborative Group (18, 21) directly linked local recurrence to survival, placing great emphasis on the surgeon's role in minimizing local recurrence by obtaining adequate margins.Breast tumor reexcisions are accompanied by a number of undesirable problems: The completion of therapy is delayed, infection rates are increased, cost is increased, there can be a negative psychological impact on the patient, and there can be diminished aesthetic outcomes (22-24). The development of an intraoperative technique that allows the fast and accurate ident...

Section: Resultsmentioning

confidence: 99%

“…lipid profiles associated with different human cancers have been investigated by DESI-MSI (55)(56)(57)(58). Moreover, the grades and subtypes of human brain tumors have been discriminated using this technique.…”

mentioning

confidence: 99%

Application of desorption electrospray ionization mass spectrometry imaging in breast cancer margin analysis

Calligaris

Caragacianu

Liu

et al. 2014

217

202

“…We have recently shown that desorption electrospray ionization (DESI) MS is a powerful methodology for characterizing lipids within tumor specimens (3)(4)(5)(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.…”

mentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

Santagata

Eberlin

Norton³

et al. 2014

232

206

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,...

“…This technique has been used for characterizing molecules such as proteins, peptides, lipids, and metabolites in tissue samples (17)(18)(19)(20)(21)(22)(23)(24). Desorption electrospray ionization (DESI) coupled with MSI has already been shown to distinguish cancerous from noncancerous tissue, and studies validating its implementation in an operating room for real-time and near-real-time diagnosis have been presented (25)(26)(27)(28). Matrix assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) has also shown great promise in supporting approaches already used in clinical diagnostic practice (29)(30)(31)(32).…”

Section: Significancementioning

confidence: 99%

MALDI mass spectrometry imaging analysis of pituitary adenomas for near-real-time tumor delineation

Calligaris

Feldman

Norton

et al. 2015

We present a proof of concept study designed to support the clinical development of mass spectrometry imaging (MSI) for the detection of pituitary tumors during surgery. We analyzed by matrix-assisted laser desorption/ionization (MALDI) MSI six nonpathological (NP) human pituitary glands and 45 hormone secreting and nonsecreting (NS) human pituitary adenomas. We show that the distribution of pituitary hormones such as prolactin (PRL), growth hormone (GH), adrenocorticotropic hormone (ACTH), and thyroid stimulating hormone (TSH) in both normal and tumor tissues can be assessed by using this approach. The presence of most of the pituitary hormones was confirmed by using MS/MS and pseudo-MS/MS methods, and subtyping of pituitary adenomas was performed by using principal component analysis (PCA) and support vector machine (SVM). Our proof of concept study demonstrates that MALDI MSI could be used to directly detect excessive hormonal production from functional pituitary adenomas and generally classify pituitary adenomas by using statistical and machine learning analyses. The tissue characterization can be completed in fewer than 30 min and could therefore be applied for the nearreal-time detection and delineation of pituitary tumors for intraoperative surgical decision-making. mass spectrometry imaging | pituitary | molecular pathology | intrasurgical diagnosis | in-source decay