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Empowering Clinical Diagnostics with Mass Spectrometry
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Cite this: ACS Omega 2020, 5, 5, 2041–2048
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https://doi.org/10.1021/acsomega.9b03764
Published January 30, 2020

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Abstract

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The unmet need for highly accurate methods of disease diagnosis poses new challenges for developments in laboratory medicine. Advances in mass spectrometry (MS)-based disease biomarker discoveries are continuously expanding the clinical diagnostic landscape. Although a number of MS-based in vitro diagnostics are already adopted in routine clinical practices, more are expected to undergo transition from bench to bedside in the near future. The ultrahigh sensitivity, specificity, and low turnaround time in molecular detection by MS make this technology highly powerful in disease detection and therapy monitoring. This mini-review highlights how MS has created a new paradigm in clinical diagnosis, which is growing in importance for public health.

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Accurate and rapid performance of medical diagnostic tests is greatly desired to foster clinical decision making and improve human healthcare. The continuous development of new analytical methods and techniques over the last five decades has made a dramatic impact on disease detection and therapeutic treatments. While the majority of in vitro diagnostics involves immunoassays to detect the target analyte, some limitations of this method (cross-reactivity, low sensitivity, limited dynamic range, and often expensive and time-consuming processing) make us pay attention to better solutions with alternative approaches, which should be highly sensitive and specific and offer high throughput. Lately, much excitement has met the news that mass spectrometry (MS) can outperform traditional chemical/biochemical measurements in diagnostic molecular pathology with its ultrahigh sensitivity that can go up to the femtomolar range. (1) MS technologies are continuously evolving with new ion source design, enhancement of resolution and sensitivity, and miniaturization over more than a hundred years since its first invention by J. J. Thomson. Increased automation and reduced architectural complexity, size, and cost of different types of MS instruments also promise easy housing and operation. Introduction of electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry in the late 1980s had laid the foundation for large protein detection. Coupling liquid chromatography with ESI mass spectrometry (LC-MS) added another dimension to the analysis of the crude biological mixture in less time. Since then, enormous success in accurate measurement and identification of endogenous biomolecules helped in deciphering the biological mechanism of disease progression and pinpointing the potential biomarkers associated with a disease. MS-based discoveries of new diagnostic biomarkers have played increasingly important roles in disease risk assessment, screening, prognosis, therapy selection, and monitoring. The recent development of ambient ionization mass spectrometry has enabled direct analysis of biological samples (blood, urine, tissue, saliva, sweat, skin, and exhaled breath gases) with little or no sample pretreatment, providing the increased utility of the MS through rapid in situ approaches. This also opens opportunities to invoke MS as a point-of-care (POC) device in the clinical setting for rapid detection of biomarkers, while the patient is on the site, enabling early-stage diagnosis and quick medical decision-making. In this context, miniature MS systems are highly desired for their easy implementation in the field (e.g., in ambulances and health camps) and at the bedside, expanding the use of biomarkers for POC diagnostics. Indeed, recent developments of hand-held/palm-portable (weight ∼1.5 kg) and several other types (weight <15 kg) of miniature MS systems equipped with different types of mass analyzers (quadrupole, cylindrical, rectilinear, and toroidal ion traps) drive their potential for clinical integration at the POC. (2,3) Though clinical implementations of these miniature MS devices are at the early stage, assessment of their POC performance needs to be evaluated in terms of their reduced cost and size, improved detection limit and ranges, automation, robustness, versatility, and integration with ambient ionization sources.
The nature of ionization also plays a crucial role in discovering disease biomarkers of various sizes and polarities (Figure 1). After the introduction of electron ionization (EI) by Arthur J. Dempster in 1918, several types of other ionization methods have been developed in the last hundred years for mass spectrometric sampling. The classic methods, which have been used for several years, are EI and chemical ionization (CI). However, these techniques are not found to be used much for clinical diagnostics in modern days because of their limitations in analyzing a wide range of polar biomolecules. Most of the mass-spectrometry-based clinical applications nowadays use MALDI, ESI, atmospheric pressure chemical ionization (APCI), and different types of ambient ionization (AI) sources. Figure 1 shows application ranges of different types of ionization techniques in discovering biomarkers of different sizes and polarities. For example, MALDI and ESI provide excellent coverage of a wide range of molecules, especially the large biomolecules (e.g., proteins), whereas APCI and AI generally examine small metabolites and lipids in the biological sample.

Figure 1

Figure 1. Portrayal ranges of different ionization techniques in the discovery of biomarkers of various molecular weights and polarity.

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MALDI- and LC-MS in Clinical Laboratories

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The recent “omics revolution” for biomarker discovery is largely being influenced by the robust performance of soft ionization MS techniques, such as MALDI- and LC-ESI-MS. An enormous amount of work on biological and clinical mass spectrometry, particularly in the last three decades, is unleashing the power of these MS techniques for their ubiquitous role in healthcare. Figure 2 shows the workflow, which is often followed in clinical diagnostics based on MALDI- or LC-MS (often through the ESI interface). Indeed, in the past ten years, the US Food and Drug Administration (FDA) has approved a number of these MS-based in vitro diagnostic methods for the identification of microbes, newborn screening (NBS), quantification of therapeutic drugs in the circulation, and vitamin D assay.

Figure 2

Figure 2. Schematic overview of the workflow in clinical diagnosis based on mass spectrometry (MALDI-MS or LC-ESI-MS).

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The microbial recognition by a benchtop MS (Bruker MALDI Biotyper CA) has revolutionized the way the pathogenic microbes are identified from the culture of human specimens. (4) This MS device intercepts characteristic proteome fingerprints of the microorganism colonies and matches them against the reference library spectra to detect it. Thus, the system has gained the ability to identify more than 400 clinically relevant bacteria and yeast species covering nearly 98% of typical bacterial identification tests done conventionally. This has also attained accuracy comparable to that of a nucleic acid sequencing method, but speed, easy operation, robustness, and cost-effectiveness of the MS method can achieve widespread implementation of this technique in microbial testing in the near future.
Likewise, liquid chromatography-tandem mass spectrometry (LC-MS/MS) has emerged as a powerful technique for the simultaneous detection of multiple amino acids, free carnitine, and acylcarnitines from the dried blood spot, providing critical information about inborn errors of metabolism. (5) This MS-based method can successfully screen more than 50 different metabolic disorders in one rapid test. This is strikingly different from the conventional enzyme- or immunoassays, which required one test to detect one disorder. Thus, LC-MS/MS has invoked a radical change in newborn screening (NBS), which is routinely being used in many counties. This has significantly contributed to the prevention and medical intervention of many metabolic disorders before they become symptomatic.
Another success of the LC-MS/MS technique in clinical diagnosis is therapeutic drug monitoring, especially the quantification of immunosuppressant drugs in blood, which have a narrow therapeutic index. (6) Often this method is applied to estimate the concentration of cyclosporine, tacrolimus, sirolimus, and mycophenolic acid to control their levels in the blood to avoid toxicity and organ rejection during the transplantation. Although immunoassays can be performed here, MS is preferred because of its greater specificity.
Analysis of vitamin D levels in serum by LC-MS/MS is now a gold standard method in clinical laboratories. (7) While immunoassays cannot distinguish between 25-hydroxy vitamins D2 and D3, the MS method can separately quantify them with high accuracy. Information on a person’s vitamin D status is important as the deficiency of the same is linked to several skeletal disorders and other diseases. Furthermore, the mass spectrometric study of vitamin D metabolism is tremendously contributing to unraveling the pathophysiology of vitamin D related diseases as well.
The well-documented superiority of the LC-MS/MS technique over traditional immunoassays is often noticed in the literature, which investigates steroids for diagnosing several endocrine disorders. (1) Immunoassays often result in the overestimation of those steroids because of cross-reactivity. In contrast, the high specificity of the LC-MS/MS method can successfully analyze steroid hormones with high accuracy. Assessment of thyroid function is crucial in endocrinology. Similarly, the LC-MS/MS technique allows rapid evaluation of thyroid hormones following the isotope dilution method, which can outperform the conventional gold standard equilibrium dialysis method by its speed and sensitivity. These impressive diagnostic capabilities of MS in endocrinology should find potential routine applications in clinics soon. However, many such MS-based endocrinology tests can be found as laboratory-developed tests (LDT) in several companies/institutes in the US.
It is also important to note that the choice of MS instrument varies depending on the clinical application. For example, a triple-quadrupole mass spectrometer coupled to LC is often the choice for quantitative analysis of most of the small molecules for NBS, therapeutic drug monitoring, vitamin D, and steroid assays. A MALDI-TOF (time-of-flight) mass spectrometer is generally used for clinical microbiology as mentioned above.
Although the above selected MS applications in disease diagnosis are followed in several hospitals and clinical settings across the world, there are many more potential MS-based diagnostic tests, which show great promise for the future of laboratory medicine and pathology. The discovery of several diagnostic biomarkers through omics study of blood and tissue samples using MS technology has opened up a new avenue in clinical diagnosis. Several tumor biomarkers, thus, have been identified through intensive research and are awaiting their validation in cohort studies and clinical trials. Evaluation of endogenous metabolic profiles by MS has also demonstrated the usefulness of this technique in disease detection.
In the last two decades, significant trends have been observed in succeeding with artificial intelligence (machine learning) to recognize the complex pattern of omics data recorded by MS for classifying disease and healthy states. In this method, often a training set is first constructed by mining complex MS data (supervised learning) from samples with known pathology (e.g., unhealthy vs healthy) to develop a statistical classifier, which can be further tested with a cross-validation process to access the predictive accuracy within the training set. The performance of the classifier is also judged by applying that to the independent validation set of samples, propelling the discovery of MS diagnostic patterns and therapeutic targets from the omics data. This machine learning approach typically includes (a) dimensionality reduction by decreasing the number of random variables (ion signals), (b) clustering classification to organize ion signals with common characteristics into different groups, (c) density estimation which analyzes ion signals in specific space, and (d) regression analysis to recognize the ion signal patterns for developing the predictive model. More details of the method can be found somewhere else in the literature. (8) This pattern recognition approach avoids the tedious job of finding a single or a few biomarkers. Rather, evaluating all MS ion signals (hundreds to thousands) as biomarkers in this process lends much more predicting power of the data, accurately providing the diagnostic information. These types of artificial intelligence-based bioinformatics systems are also found to be vigilant, adaptive, and appropriate to handle the huge dimensionality of omics data, and they also remain open to gain experience through the constant flow of information from the training samples. This MS-based omics pattern diagnosis is also thought to have important implications in detecting diseases at a very early stage when slight but significant molecular dysregulation cascades, and crosstalk specific to a disease is set off.

Ambient Ionization MS: The Future of POC Diagnostics

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The development of ambient ionization mass spectrometry (AIMS) is another game-changing invention for rapid disease diagnosis with almost no sample pretreatment. (9,10) This ionization probe can be directly applied to live organs, skins, tissues, biological fluids, and volatiles open to the air (ambient conditions), aiding instantaneous capture of molecular fingerprints from those samples. Different variants of AIMS have been developed after its first introduction as desorption electrospray ionization mass spectrometry (DESI-MS) in 2004. (11)Figure 3 represents some of the most promising AIMS, which could ignite a revolution in disease detection. Table 1 summarizes the emerging applications of these AIMS in humans for gaining crucial diagnostic information in a very short time at a much lower cost.

Figure 3

Figure 3. Schematic diagrams of (a) desorption electrospray ionization mass spectrometry (DESI-MS), (b) paper spray ionization mass spectrometry (PSI-MS), (c) touch spray ionization mass spectrometry (TSI-MS), (d) extractive electrospray ionization mass spectrometry (EESI-MS), (e) rapid evaporative ionization mass spectrometry (REIMS) or iKnife, (f) MassSpec Pen, (g) direct analysis in real-time mass spectrometry (DART-MS), and (h) matrix-assisted laser desorption electrospray ionization mass spectrometry (MALDESI-MS).

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Table 1. Use of Some Ambient Ionization Mass Spectrometry Techniques (Figure 3) for the Diagnostic Study in Humans
techniqueyear of inceptiontype of diagnosisreferences
DESI-MS2004distinguishing cancer and normal specimens, determining cancer aggressiveness and grades, molecular typing of cancer, identifying cancer biomarkers, intraoperative cancer margin assessment, visualizing dermal penetration of sodium channel modulator, acquiring personal information (genders, ethnicities, and ages) from latent fingerprints. (9,10,12,13,17,21)
PSI-MS2010therapeutic drug monitoring and newborn screening from dried blood spot (10,14,15)
TSI-MS2014therapeutic drug monitoring from blood, cancer diagnosis, identification of bacteria from throat swab (10,16,17)
EESI-MS2006skin and breath metabolite detection (10,18)
REIMS/iKnife2009intraoperative tissue identification, classification of the tumor and healthy specimens from different organs (10,19,20)
MassSpec Pen2017rapid discrimination of cancer from normal specimens (3)
DART-MS2005metabolic fingerprinting and quantification (10,22)
MALDESI-MS2006mapping the distribution of endogenous and exogenous (drugs) compounds in tissue specimens (23)
DESI-MS (Figure 3a) uses a stream of high-speed charged microdroplets to strike the sample (say tissue) surface extracting and transferring molecular species from the sample to the splashed microdroplets, which subsequently undergo evolution to form charged gaseous species to be detected by the MS. (11) The DESI experiment can be performed in seconds with minimal or no sample preparation. These characteristics of DESI enable high-throughput analysis of varieties of samples like biopsy specimens, pharmaceutical formulations (tablets, ointments, etc.), and biofluids spotted onto filter paper. DESI-MS can also be operated in two dimensions by scanning the tissue surface in x and y directions, allowing detailed biochemical (lipids, metabolites, etc.) mapping of the tissue. (9,12,13) The remarkable success of this label-free molecular imaging technique in rapidly evaluating biopsy specimens promises to employ DESI-MSI as a next-generation histopathology technique (discussed later).
Paper spray ionization mass spectrometry (PSI-MS) is another variant of AIMS (Figure 3b). (14) PSI-MS is often used for analyzing a dried sample (e.g., biofluid) spot on a small triangular filter paper, which is clipped to a high-voltage power supply in front of a mass spectrometer. Upon dispensing a spray solvent, analytes are electrosprayed from the sample spot followed by their detection by the mass spectrometer. Thus, human blood, urine, and tissues can be sampled rapidly through this technique under ambient conditions for mass spectrometric analysis (Table 1). These characteristics could make PSI-MS an ideal point of care device for disease detection and clinical diagnosis as the whole workflow, starting from loading the sample to reporting the result, merely takes a few minutes. (10) To date, however, the most widespread clinical use of PSI-MS has been for qualitative and quantitative detection of therapeutic drugs in blood, which can be useful in pharmacokinetics and toxicokinetics studies. (10,15)
Touch spray ionization mass spectrometry (TSI-MS) is a minor modification of PSI-MS, where instead of a paper generally a metallic teasing needle is used for sample loading (Figure 3c). (10,16,17) Simple touching of the needle tip with the sample (tissue, blood, throat swab, etc.) causes absorption of analytes in the needle tip, which is then clipped to a high-voltage power source, and the rest of the operation is similar to the PSI source as described above. This convenient and rapid sampling makes TSI-MS remarkably attractive for having low invasiveness and high-throughput performance in blood and tissue analysis (Table 1).
Extractive electrospray ionization mass spectrometry (EESI-MS) works by the fusion of two streams of aerosols, one of which is generated by ESI (Figure 3d). (10,18) The sample (urine, serum, exhaled breath, etc.) is nebulized to form aerosol droplets, which are bombarded with the electrospray (ES) droplets, causing coalescence through liquid–liquid extraction. Subsequent droplet evolution by the ES process produces gaseous charged analytes for mass spectrometric detection (Table 1). Rapid in vivo analysis of living objects (e.g., skin) using EESI-MS has been shown to have potential applications in clinical diagnosis and homeland security. (10)
Rapid evaporative ionization mass spectrometry (REIMS) is another breakthrough in AIMS (Figure 3e). (19,20) In REIMS, generally, a heated electrosurgical probe is applied to a tissue to generate a smoke of gaseous ions (generally lipid ions), which are afterward transferred to a mass spectrometer through a flexible tube and Ventury air jet pump. This allows REIMS to provide us in vivo and ex vivo diagnostic information in real time. (20) The recent innovation of intelligent knife (iKnife) for cancer surgery is based on REIMS technology. iKnife helps surgeons in determining the cancer resection margin intraoperatively, while the same is applied for cancer ablation simultaneously. The groundbreaking success of iKnife in distinguishing cancer and normal tissues provides a strong platform for its clinical adoption in cancer surgery soon.
The latest invention of a MassSpec pen (Figure 3f) also has huge promise in rapid discrimination of cancer from normal tissues by reading the biochemical signature within ten seconds. (3) A MassSpec pen is a hand-held 3D-printed pen consisting of three ports: the incoming port for the delivery of a water droplet, a central port for gas delivery, and the outgoing port for transporting the water droplet containing a biochemical cocktail to the mass spectrometer. Once the pen tip is in contact with the tissue for a few seconds, the water droplet can extract and transfer biomolecules from the tissue to the mass spectrometer. Two important characteristics, e.g., speed and sensitivity, make this pen highly promising to identify the cancer margin rapidly and intraoperatively for complete resection of the tumor. (21)
DART (direct analysis in real-time) is another versatile ambient ionization technique (Figure 3g), which can ionize species directly desorbed from the sample surface (tablets, biofluids, living organisms, etc.), followed by their mass spectrometric detection. The electrical discharge in the DART ion source delivers excited-state gaseous atoms (e.g., metastable helium), which ionize the surrounding (atmospheric) gases and eventually the analyte species through ion–molecule reaction. As DART can be used in the open environment to analyze samples in their native states (solid, liquid, and gases), this technique promises its widespread implementation for clinical and pharmacological analysis (Table 1) or as a POC device. (22)
Matrix-assisted laser desorption electrospray ionization (MALDESI) is the hybrid ambient ionization technique combining laser ablation and electrospray post ionization as illustrated in Figure 3h. Upon laser irradiation, the neutral analyte species are desorbed from the sample surface. The plume of these desorbed analytes is allowed to interact with an orthogonal electrospray plume in front of a mass spectrometer. This causes analyte charging by the ESI-like process followed by their mass spectrometric detection. Originally UV laser was used in this ionization, but recently the use of a mid-infrared (IR) laser has been invoked (IR-MALDESI). (23) The most common clinical application of MALDESI is the assessment of the distribution of endogenous and exogenous species in the tissue specimens (Table 1). If no matrix is applied for the above ionization, the technique is called electrospray-assisted laser desorption/ionization (ELDI) when UV laser is used or laser ablation electrospray ionization (LAESI) when IR laser is used. Both of these techniques have been used for ex vivo tissue imaging.

Imaging Mass Spectrometry for Disease Diagonsis

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Mass spectrometry imaging (MSI) is a powerful emerging analytical technique that allows simultaneous visualization of the spatial distribution of hundreds of biomolecules (metabolites, lipids, peptides, proteins, etc.) across the tissue specimen without labeling them. DESI and MALDI are the most common ionization techniques used in MSI to desorb analyte species from the tissue surface. (9,13,23) Thus, the imaging experiment is performed by scanning the tissue surface in 2D followed by the pixel-to-pixel recording of the mass spectral data, which are plotted finally to construct the ion images. Thus, one MSI scan enables the visualization of hundreds of biomolecules, whatever detected. MSI has great implication in the disease pathology. For example, MSI can be used to pinpoint the biomarker localization in the tissue section for discriminating cancer and normal specimens, evaluating tumor margins from the excision biopsies and diagnosing several other diseases. (9,12,13,17,21) While DESI-MSI has the ability to map the distribution of small molecules (metabolites, lipids, etc.), MALDI-MSI can image the distribution of relatively large molecules (peptides, lipids, etc.) and proteins in the tissue. However, DESI has a major advantage over MALDI, particularly because, unlike MALDI, DESI requires minimal sample preparation and does not need a vacuum chamber or an enclosure for ionization. DESI can be operated under ambient conditions (open-air sampling) rapidly to acquire the molecular information in almost real-time. DESI-MSI can be applied to a fresh tissue section or even live organ/skin without any pretreatment. Being less destructive (when the appropriate solvent spray is used), the same section can be evaluated by conventional histopathology (H&E) after its DESI-MSI study. The H&E images can be overlaid with the metabolite/lipid ion map to empower DESI-MSI in understanding the metabolic signature of the healthy and unhealthy tissue. Figure 4 presents an example of diagnosing prostate cancer using DESI-MSI. A typical surgically resected prostate specimen (Figure 4a) was evaluated by a genitourinary pathologist to delineate the areas of cancerous (red outline) and normal (black outline) tissue. DESI-MSI of the adjacent section (Figure 4b) shows the differential distributions of PS(18:0/18:1) (m/z 788.5409) and PA(20:4/17:0) (m/z 709.4778) in cancer and normal cells. While the former (PS) was found to be downregulated, the later (PA) was upregulated in the cancerous area of the tissue. (21) Our recent study also revealed that the DESI-MS measurement of glucose and citrate levels can accurately predict the prostate cancer margin rapidly (Figure 4c). (24) Further, the application of unsupervised or supervised statistical methods in MSI data pattern recognition can perform well in discriminating the healthy and unhealthy tissues with a very high agreement with the conventional gold standard histopathology (H&E and immune histopathology, etc.). (9) Although much of the studies on humans using DESI-MSI focused on cancer, (9) the performance of this technique in other diseases (renal, infectious, skin, fertility, transplantation, and metabolic diseases), where tissue analyses are involved, needs to be evaluated in the future. It should be noted that the spatial resolution of DESI-MS images is ∼150–200 μm, which compares well with the thickness of a surgical knife. However, much lower spatial resolution (∼20 μm) can be achieved using MALDI-MSI. Indeed, MALDI-MSI also emerged as a valuable tool with several clinical applications like localizing proteins, mapping the distribution of lipids and neuropeptides at both organ and cellular levels in the context of biomarker discovery, diagnosis, and prognosis of different diseases. (23,25) Overall, great sensitivity, chemical specificity, fairly high spatial resolution, and multiplex molecular information make MSI a powerful medical imaging technique, which could serve as a useful adjunct to histology for disease diagnosis.

Figure 4

Figure 4. (a) H&E of a prostate tissue specimen that contains both normal (black outline) and cancer (red outline) areas. (b) Negative ion mode DESI-MSI of the adjacent section (15 μm thickness) mapping the differential distribution of a phosphatidic acid (m/z 709.4778) and a phosphatidylserine (m/z 788.5409) throughout the tissue (overlaid image in bicolor), distinguishing the areas of cancer and normal. (c) Extracted ion chronograms of glucose and citrate over a line scan of a typical prostate tissue specimen (H&E shown in the inset) that contains both normal (black outline) and cancer (red outline) areas. (24)

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Excitements, Challenges, and Limitations to Overcome

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All told, mass spectrometry has opened a new window in the clinical laboratory with its remarkable sensitivity and specificity, which is often not produced by other analytical techniques. Although MS is still underutilized in various clinical settings, it has the potential to extend the current capabilities of disease detection with its high level of accuracy, precision, and reproducibility. Continuous advancements in making MS more robust with various types of automation and robotics also warrant its high-throughput performance with affordable cost-to-benefit balance. From the NBS study, this is now well understood that a single MS test can detect multiple diseases. Therefore, MS can be viewed as a next-generation pathology technique for acquiring multiple pathological information, characteristic of various diseases, in a single test, reducing the financial and technical drain on hospital resources. The development of AIMS has brought a revolution, which is anticipating progression from the time-consuming LC-MS approach to the rapid spatially resolved in situ approach. The use of artificial intelligence in pattern recognition of a huge data set recorded by AIMS lends much more predictive power than that in evaluating the signal of a few diagnostic biomarkers. AIMS has been particularly useful in rapid cancer margin analysis intraoperatively, which is critically needed to augment the success rate of frozen section analysis and to circumvent the need for time in extensive sample processing in conventional histopathology during surgery. The near-future availability of low-cost miniature or hand-held mass spectrometers is likely to play an important role in clinics for the development of POC devices. Taming MS software packages by machine learning algorithms to read the MS data as a “barcode of the disease” should aid the smooth transition of the MS from bench to bedside. Considering all those capabilities, mass spectrometry is appearing as a technique of obvious public health importance, although there could be mixed feelings and anxieties in the clinical diagnostic community as MS could outperform several traditional diagnostic methods. However, cohort studies and clinical trials of many MS-based diagnostic methods should be undertaken on different populations (countries) for their transition from discovery-based approaches to standard clinical practices. Despite the remarkable promise, one of the major limitations of the clinical MS to date is the identification of blood biomarkers for the detection of a disease (say cancer) at a very early stage, when a few maker molecules are released in circulation. So far, most of the MS-based clinical studies have been conducted when the disease is well manifested. This limitation needs to be overcome by appropriate subject selection for the clinical study at the onset of the disease. A biomarker can also present the epiphenomena of a disease, or it could also be found in a similar presentation of a disease. This also needs to be clarified before the clinical practice with the biomarker. Therefore, there are still challenges to overcome in this aspect though we can be optimistic that there should be several MS-based clinical assays approved soon by healthcare regulatory authorities.

Author Information

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    • Notes
      The author declares no competing financial interest.

    Biography

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    Shibdas Banerjee completed his M.Sc in chemistry at the Indian Institute of Technology (IIT), Roorkee, India, in 2008 and Ph.D. in chemistry at the Tata Institute of Fundamental Research (TIFR), Mumbai, India, in 2014. He worked as a postdoctoral research associate in the laboratory of Prof. Richard N. Zare, Stanford University, USA, from 2014 to 2017. He is currently an assistant professor in the Department of Chemistry, Indian Institute of Science Education and Research (IISER), Tirupati, India.

    Acknowledgments

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    The author is thankful to the Science and Engineering Research Board, Department of Science and Technology, Government of India, for providing a Ramanujan Fellowship Research Grant (SB/S2/RJN-130/2017) and Early Career Research Award (ECR/2018/001268).

    References

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      Ombrone, Daniela; Giocaliere, Elisa; Forni, Giulia; Malvagia, Sabrina; la Marca, Giancarlo
      Mass Spectrometry Reviews (2016), 35 (1), 71-84CODEN: MSRVD3; ISSN:0277-7037. (John Wiley & Sons, Inc.)
      Tandem mass spectrometry (MS/MS) has become a leading technol. used in clin. chem. and has shown to be particularly sensitive and specific when used in newborn screening (NBS) tests. The success of tandem mass spectrometry is due to important advances in hardware, software and clin. applications during the last 25 years. MS/MS permits a very rapid measurement of many metabolites in different biol. specimens by using filter paper spots or directly on biol. fluids. Its use in NBS give us the chance to identify possible treatable metabolic disorders even when asymptomatic and the benefits gained by this type of screening is now recognized worldwide. Today the use of MS/MS for second-tier tests and confirmatory testing is promising esp. in the early detection of new disorders such as some lysosomal storage disorders, ADA and PNP SCIDs, X-adrenoleucodistrophy (X-ALD), Wilson disease, guanidinoacetate methyltransferase deficiency (GAMT), and Duchenne muscular dystrophy. The new challenge for the future will be reducing the false pos. rate by using second-tier tests, avoiding false neg. results by using new specific biomarkers and introducing new treatable disorders in NBS programs.
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      Jannetto, P. J. Chapter 8 - Therapeutic drug monitoring using mass spectrometry. In Mass Spectrometry for the Clinical Laboratory; Nair, H., Clarke, W., Eds.; Academic Press: San Diego, 2017; pp 165– 179.
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      Volmer, D. A.; Mendes, L. R. B. C.; Stokes, C. S. Analysis of vitamin D metabolic markers by mass spectrometry: Current techniques, limitations of the “gold standard” method, and anticipated future directions. Mass Spectrom. Rev. 2015, 34 (1), 2– 23,  DOI: 10.1002/mas.21408
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      Analysis of vitamin D metabolic markers by mass spectrometry: Current techniques, limitations of the "gold standard" method, and anticipated future directions
      Volmer, Dietrich A.; Mendes, Luana R. B. C.; Stokes, Caroline S.
      Mass Spectrometry Reviews (2015), 34 (1), 2-23CODEN: MSRVD3; ISSN:0277-7037. (John Wiley & Sons, Inc.)
      A review. Vitamin D compds. belong to a group of secosteroids, which occur naturally as vitamin D3 in mammals and D2 in plants. Vitamin D is vital for bone health but recent studies showed a much wider role in the pathologies of diseases such as diabetes, cancer, autoimmune, neurodegenerative, mental and cardiovascular diseases. Photosynthesis of vitamin D in the human skin and subsequent hepatic and renal metab. generate a wide range of transformation products occurring over a large dynamic range spanning from picomolar to nanomolar levels. This necessitates selective and sensitive anal. methods to quant. capture these low concn. levels in relevant tissues such as blood. Ideally, vitamin D assessment would be performed using a universal and standardized anal. method available to clin. labs. that provides reliable and accurate quant. results for all relevant vitamin D metabolites with sufficiently high throughput. At present, LC-MS/MS assays are the most promising techniques for vitamin D anal. The present review focuses on developments in mass spectrometry methodologies of the past 12 years. It will highlight detrimental influences of the biol. matrix, epimer contributions, pitfalls of specific mass spectrometry data acquisition routines (in particular multiple reaction monitoring, MRM), influence of ionization source, derivatization reactions, inter-lab. comparisons on precision, accuracy, and application range of vitamin D metabolites. © 2013 Wiley Periodicals, Inc. Mass Spec Rev 34: 2-23, 2015.
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      Perakakis, N.; Yazdani, A.; Karniadakis, G. E.; Mantzoros, C. Omics, big data and machine learning as tools to propel understanding of biological mechanisms and to discover novel diagnostics and therapeutics. Metab., Clin. Exp. 2018, 87, A1– A9,  DOI: 10.1016/j.metabol.2018.08.002
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      Omics, big data and machine learning as tools to propel understanding of biological mechanisms and to discover novel diagnostics and therapeutics
      Perakakis, Nikolaos; Yazdani, Alireza; Karniadakis, George E.; Mantzoros, Christos
      Metabolism, Clinical and Experimental (2018), 87 (), A1-A9CODEN: METAAJ; ISSN:0026-0495. (Elsevier)
      A review summarizing the most important "omics" procedures and describe the current challenges related to their use. Addnl., we describe the novel methods of data-mining and machine learning anal., and particularly, how they can be used in a hierarchical manner to produce robust results for medicine from big data.
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      Banerjee, S. Ambient ionization mass spectrometry imaging for disease diagnosis: Excitements and challenges. J. Biosci. 2018, 43 (4), 731– 738,  DOI: 10.1007/s12038-018-9785-y
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      Ambient ionization mass spectrometry imaging for disease diagnosis: Excitements and challenges
      Banerjee, Shibdas
      Journal of Biosciences (New Delhi, India) (2018), 43 (4), 731-738CODEN: JOBSDN; ISSN:0250-5991. (Springer (India) Private Ltd.)
      A review. Tissue anal. in histol. is extremely important and also considered to be a gold std. to diagnose and prognosticate several diseases including cancer. Intraoperative evaluation of surgical margin of tumor also relies on frozen section histopathol., which is time consuming, challenging and often subjective. Recent development in the ambient ionization mass spectrometry imaging (MSI) technique has enabled us to simultaneously visualize hundreds to thousands of mols. (ion images) in the biopsy specimen, which are strikingly different and more powerful than the single optical tissue image anal. in conventional histopathol. This paper will highlight the emergence of the desorption electrospray ionization MSI (DESI-MSI) technique, which is label-free, requires minimal or no sample prepn. and operates under ambient conditions. DESI-MSI can record ion images of lipid/metabolite distributions on biopsy specimens, providing a wealth of diagnostic information based on differential distributions of these mol. species in healthy and unhealthy tissues. Remarkable success of this technol. in rapidly evaluating the cancer margin intraoperatively with very high accuracy also promises to bring this imaging technique from bench to bedside.
    10. 10
      Li, L.-H.; Hsieh, H.-Y.; Hsu, C.-C. Clinical Application of Ambient Ionization Mass Spectrometry. Mass Spectrom. 2017, 6 (2), S0060– S0060,  DOI: 10.5702/massspectrometry.S0060
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      Clinical application of ambient ionization mass spectrometry
      Li, Li-Hua; Hsieh, Hua-Yi; Hsu, Cheng-Chih
      Mass Spectrometry (2017), 6 (2Spec.Iss.), S0060/1-S0060/12CODEN: MSAPG5; ISSN:2187-137X. (Mass Spectrometry Society of Japan)
      Ambient ionization allows mass spectrometry anal. directly on the sample surface under atm. pressure with almost zero sample pretreatment. Since the development of desorption electrospray ionization (DESI) in 2004, many other ambient ionization techniques were developed. Due to their simplicity and low operation cost, rapid and on-site clin. mass spectrometry anal. becomes real. In this review, we will highlight some of the most widely used ambient ionization mass spectrometry approaches and their applications in clin. study.
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      Takáts, Z.; Wiseman, J. M.; Gologan, B.; Cooks, R. G. Mass Spectrometry Sampling Under Ambient Conditions with Desorption Electrospray Ionization. Science 2004, 306 (5695), 471– 473,  DOI: 10.1126/science.1104404
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      Mass Spectrometry Sampling Under Ambient Conditions with Desorption Electrospray Ionization
      Takats, Zoltan; Wiseman, Justin M.; Gologan, Bogdan; Cooks, R. Graham
      Science (Washington, DC, United States) (2004), 306 (5695), 471-473CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      A new method of desorption ionization is described and applied to the ionization of various compds., including peptides and proteins present on metal, polymer, and mineral surfaces. Desorption electrospray ionization (DESI) is carried out by directing electrosprayed charged droplets and ions of solvent onto the surface to be analyzed. The impact of the charged particles on the surface produces gaseous ions of material originally present on the surface. The resulting mass spectra are similar to normal ESI mass spectra in that they show mainly singly or multiply charged mol. ions of the analytes. The DESI phenomenon was obsd. both in the case of conductive and insulator surfaces and for compds. ranging from nonpolar small mols. such as lycopene, the alkaloid coniceine, and small drugs, through polar compds. such as peptides and proteins. Changes in the soln. that is sprayed can be used to selectively ionize particular compds., including those in biol. matrixes. In vivo anal. is demonstrated.
    12. 12
      Eberlin, L. S.; Dill, A. L.; Golby, A. J.; Ligon, K. L.; Wiseman, J. M.; Cooks, R. G.; Agar, N. Y. R. Discrimination of Human Astrocytoma Subtypes by Lipid Analysis Using Desorption Electrospray Ionization Imaging Mass Spectrometry. Angew. Chem., Int. Ed. 2010, 49 (34), 5953– 5956,  DOI: 10.1002/anie.201001452
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      Discrimination of Human Astrocytoma Subtypes by Lipid Analysis Using Desorption Electrospray Ionization Imaging Mass Spectrometry
      Eberlin, Livia S.; Dill, Allison L.; Golby, Alexandra J.; Ligon, Keith L.; Wiseman, Justin M.; Cooks, R. Graham; Agar, Nathalie Y. R.
      Angewandte Chemie, International Edition (2010), 49 (34), 5953-5956, S5953/1-S5953/12CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      This study was to use desorption electrospray ionization imaging mass spectrometry (DESI-MS) to analyze and characterize the lipid profiles of different grades of human astrocytomas.
    13. 13
      Eberlin, L. S.; Ferreira, C. R.; Dill, A. L.; Ifa, D. R.; Cooks, R. G. Desorption electrospray ionization mass spectrometry for lipid characterization and biological tissue imaging. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2011, 1811 (11), 946– 960,  DOI: 10.1016/j.bbalip.2011.05.006
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      Desorption electrospray ionization mass spectrometry for lipid characterization and biological tissue imaging
      Eberlin, Livia S.; Ferreira, Christina R.; Dill, Allison L.; Ifa, Demian R.; Cooks, R. Graham
      Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2011), 1811 (11), 946-960CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B. V.)
      A review. Desorption electrospray ionization mass spectrometry (DESI-MS) imaging of biol. samples allows untargeted anal. and structural characterization of lipids ionized from the near-surface region of a sample under ambient conditions. DESI is a powerful and sensitive MS ionization method for 2D and 3D imaging of lipids from direct and unmodified complex biol. samples. This review describes the strengths and limitations of DESI-MS for lipid characterization and imaging together with the tech. workflow and a survey of applications. Included are discussions of lipid mapping and biomarker discovery as well as a perspective on the future of DESI imaging.
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      Liu, J.; Wang, H.; Manicke, N. E.; Lin, J.-M.; Cooks, R. G.; Ouyang, Z. Development, Characterization, and Application of Paper Spray Ionization. Anal. Chem. 2010, 82 (6), 2463– 2471,  DOI: 10.1021/ac902854g
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      Development, Characterization, and Application of Paper Spray Ionization
      Liu, Jiangjiang; Wang, He; Manicke, Nicholas E.; Lin, Jin-Ming; Cooks, R. Graham; Ouyang, Zheng
      Analytical Chemistry (Washington, DC, United States) (2010), 82 (6), 2463-2471CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      Paper spray is developed as a direct sampling ionization method for mass spectrometric anal. of complex mixts. Ions of analyte are generated by applying a high voltage to a paper triangle wetted with a small vol. (<10 μL) of soln. Samples can be preloaded onto the paper, added with the wetting soln., or transferred from surfaces using the paper as a wipe. It is demonstrated that paper spray is applicable to the anal. of a wide variety of compds., including small org. compds., peptides, and proteins. Procedures are developed for anal. of dried biofluid spots and applied to therapeutic drug monitoring with whole blood samples and to illicit drug detection in raw urine samples. Limits of detection of 50 ng/mL (or 20 pg abs.) are achieved for atenolol in bovine blood. The combination of sample collection from surfaces and paper spray ionization also enables fast chem. screening at high sensitivity, for example 100 pg of heroin distributed on a surface and agrochems. on fruit peels are detectable. Online derivatization with a preloaded reagent is demonstrated for anal. of cholesterol in human serum. The combination of paper spray with miniature mass spectrometers offers a powerful impetus to wide application of mass spectrometry in nonlab. environments.
    15. 15
      Chiang, S.; Zhang, W.; Ouyang, Z. Paper spray ionization mass spectrometry: recent advances and clinical applications. Expert Rev. Proteomics 2018, 15 (10), 781– 789,  DOI: 10.1080/14789450.2018.1525295
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      Paper spray ionization mass spectrometry: recent advances and clinical applications
      Chiang, Spencer; Zhang, Wenpeng; Ouyang, Zheng
      Expert Review of Proteomics (2018), 15 (10), 781-789CODEN: ERPXA3; ISSN:1478-9450. (Taylor & Francis Ltd.)
      A review. Introduction: Paper spray mass spectrometry has provided a rapid, quant. ambient ionization method for xenobiotic and biomol. anal. As an alternative to traditional sample prepn. and chromatog., paper spray demonstrates the sampling ionization of a wide range of mols. and significant sensitivity from complex biofluids. The amenability of paper spray with dried blood spots and other sampling types shows strong potential for rapid, point-of-care (POC) anal. without time-consuming sepn. procedures. Areas covered: This special report summarizes the current state and advances in paper spray mass spectrometry that relate to its applicability for clin. anal. It also provides our perspectives on the future development of paper spray mass spectrometry and its potential roles in clin. settings. Expert commentary: Paper spray has provided the fundamental aspects of ambient ionization needed for implementation at the POC. With further clin. management and standardization, paper spray has the potential to replace traditional complex anal. procedure for rapid quant. detection of illicit drugs, therapeutic drugs and metabolites. Surface and substrate modifications also offer significant improvement in desorption and ionization efficiencies, resulting in enhanced sensitivity. Comprehensive anal. of metabolites and lipids will further extend the implementation of paper spray ionization mass spectrometry into clin. applications.
    16. 16
      Kerian, K. S.; Jarmusch, A. K.; Cooks, R. G. Touch spray mass spectrometry for in situ analysis of complex samples. Analyst 2014, 139 (11), 2714– 2720,  DOI: 10.1039/C4AN00548A
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      Touch spray mass spectrometry for in situ analysis of complex samples
      Kerian, Kevin S.; Jarmusch, Alan K.; Cooks, R. Graham
      Analyst (Cambridge, United Kingdom) (2014), 139 (11), 2714-2720CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)
      Touch spray, a spray-based ambient in situ ionization method, uses a small probe, e.g. a teasing needle to pick up sample and the application of voltage and solvent to cause field-induced droplet emission. Compds. extd. from the microsample are incorporated into the sprayed micro droplets. Performance tests include disease state of tissue, microorganism identification, and therapeutic drug quantitation. Chem. derivatization was performed simultaneously with ionization.
    17. 17
      Ifa, D. R.; Eberlin, L. S. Ambient Ionization Mass Spectrometry for Cancer Diagnosis and Surgical Margin Evaluation. Clin. Chem. 2016, 62 (1), 111– 123,  DOI: 10.1373/clinchem.2014.237172
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      Ambient ionization mass spectrometry for cancer diagnosis and surgical margin evaluation
      Ifa, Demian R.; Eberlin, Livia S.
      Clinical Chemistry (Washington, DC, United States) (2016), 62 (1), 111-123CODEN: CLCHAU; ISSN:0009-9147. (American Association for Clinical Chemistry)
      BACKGROUND: There is a clin. need for new technologies that would enable rapid disease diagnosis based on diagnostic mol. signatures. Ambient ionization mass spectrometry has revolutionized the means by which mol. information can be obtained from tissue samples in real time and with minimal sample pretreatment. New developments in ambient ionization techniques applied to clin. research suggest that ambient ionization mass spectrometry will soon become a routine medical tool for tissue diagnosis. CONTENT: This review summarizes the main developments in ambient ionization techniques applied to tissue anal., with focus on desorption electrospray ionization mass spectrometry, probe electrospray ionization, touch spray, and rapid evaporative ionization mass spectrometry. We describe their applications to human cancer research and surgical margin evaluation, highlighting integrated approaches tested for ex vivo and in vivo human cancer tissue anal. We also discuss the challenges for clin. implementation of these tools and offer perspectives on the future of the field. SUMMARY: A variety of studies have showcased the value of ambient ionization mass spectrometry for rapid and accurate cancer diagnosis. Small mols. have been identified as potential diagnostic biomarkers, including metabolites, fatty acids, and glycerophospholipids. Statistical anal. allows tissue discrimination with high accuracy rates (>95%) being common. This young field has challenges to overcome before it is ready to be broadly accepted as a medical tool for cancer diagnosis. Growing research in new, integrated ambient ionization mass spectrometry technologies and the ongoing improvements in the existing tools make this field very promising for future translation into the clinic.
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      Gu, H.; Xu, N.; Chen, H. Direct analysis of biological samples using extractive electrospray ionization mass spectrometry (EESI-MS). Anal. Bioanal. Chem. 2012, 403 (8), 2145– 2153,  DOI: 10.1007/s00216-012-5874-1
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      Direct analysis of biological samples using extractive electrospray ionization mass spectrometry (EESI-MS)
      Gu, Haiwei; Xu, Ning; Chen, Huanwen
      Analytical and Bioanalytical Chemistry (2012), 403 (8), 2145-2153CODEN: ABCNBP; ISSN:1618-2642. (Springer)
      Mass spectrometry (MS) is one of the most widely used techniques for the anal. of biol. samples. In the past decade, a novel improvement in MS was the invention of ambient ionization which stands out owing to its unique capability of direct anal. of complex samples with no or minimal pretreatment. In this review, extractive electrospray ionization (EESI), a representative ambient ionization technique, is introduced focusing on its mechanism, instrumentation, and applications in biol. anal. EESI uses a traditional ESI channel to produce primary ions which subsequently ionize neutral chems. from the sample introduction channel through an online extn. process. When analyzing biol. samples, EESI has advantages of rapid anal., high matrix tolerance, and the ability to perform in vivo anal. According to previous studies, EESI is able to directly analyze various chems. in complex biol. specimens in liq., gas, and solid states. EESI can provide a sensitive and selective measurement of biol. samples for both qual. and quant. purposes. Therefore, it is anticipated that EESI will have promising applications, esp. in fields which require the fast and/or in vivo anal. of biol. samples with complicated matrixes.
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      Balog, J.; Sasi-Szabó, L.; Kinross, J.; Lewis, M. R.; Muirhead, L. J.; Veselkov, K.; Mirnezami, R.; Dezso, B.; Damjanovich, L.; Darzi, A.; Nicholson, J. K.; Takáts, Z. Intraoperative Tissue Identification Using Rapid Evaporative Ionization Mass Spectrometry. Sci. Transl. Med. 2013, 5 (194), 194ra93– 194ra93,  DOI: 10.1126/scitranslmed.3005623
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      Identifying the margin: a new method to distinguish between cancerous and noncancerous tissue during surgery
      Takats Zoltan; Denes Julia; Kinross James
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      Banerjee, S.; Manna, S. K. Assessment of Metabolic Signature for Cancer Diagnosis Using Desorption Electrospray Ionization Mass Spectrometric Imaging. In Cancer Metabolism: Methods and Protocols; Haznadar, M., Ed.; Springer New York: New York, NY, 2019; pp 275– 297.
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      Li, Y. Application of DART-MS in Clinical and Pharmacological Analysis. In Direct Analysis in Real Time Mass Spectrometry; Dong, Y., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: 2017; pp 223– 240.
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      Barry, J. A.; Robichaud, G.; Bokhart, M. T.; Thompson, C.; Sykes, C.; Kashuba, A. D. M.; Muddiman, D. C. Mapping antiretroviral drugs in tissue by IR-MALDESI MSI coupled to the Q Exactive and comparison with LC-MS/MS SRM assay. J. Am. Soc. Mass Spectrom. 2014, 25 (12), 2038– 2047,  DOI: 10.1007/s13361-014-0884-1
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      Mapping Antiretroviral Drugs in Tissue by IR-MALDESI MSI Coupled to the Q Exactive and Comparison with LC-MS/MS SRM Assay
      Barry, Jeremy A.; Robichaud, Guillaume; Bokhart, Mark T.; Thompson, Corbin; Sykes, Craig; Kashuba, Angela D. M.; Muddiman, David C.
      Journal of the American Society for Mass Spectrometry (2014), 25 (12), 2038-2047CODEN: JAMSEF; ISSN:1044-0305. (Springer)
      This work describes the coupling of the IR-MALDESI imaging source with the Q Exactive mass spectrometer. IR-MALDESI MSI was used to elucidate the spatial distribution of several HIV drugs in cervical tissues that had been incubated in either a low or high concn. Serial sections of those analyzed by IR-MALDESI MSI were homogenized and analyzed by LC-MS/MS to quantify the amt. of each drug present in the tissue. By comparing the two techniques, an agreement between the av. intensities from the imaging expt. and the abs. quantities for each drug was obsd. This correlation between these two techniques serves as a prerequisite to quant. IR-MALDESI MSI. In addn., a targeted MS2 imaging expt. was also conducted to demonstrate the capabilities of the Q Exactive and to highlight the added selectivity that can be obtained with SRM or MRM imaging expts.
    24. 24
      Banerjee, S.; Zare, R. N.; Tibshirani, R. J.; Kunder, C. A.; Nolley, R.; Fan, R.; Brooks, J. D.; Sonn, G. A. Diagnosis of prostate cancer by desorption electrospray ionization mass spectrometric imaging of small metabolites and lipids. Proc. Natl. Acad. Sci. U. S. A. 2017, 114 (13), 3334– 3339,  DOI: 10.1073/pnas.1700677114
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      24
      Diagnosis of prostate cancer by desorption electrospray ionization mass spectrometric imaging of small metabolites and lipids
      Banerjee, Shibdas; Zare, Richard N.; Tibshirani, Robert J.; Kunder, Christian A.; Nolley, Rosalie; Fan, Richard; Brooks, James D.; Sonn, Geoffrey A.
      Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (13), 3334-3339CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Accurate identification of prostate cancer in frozen sections at the time of surgery can be challenging, limiting the surgeon's ability to best det. resection margins during prostatectomy. We performed desorption electrospray ionization mass spectrometry imaging (DESI-MSI) on 54 banked human cancerous and normal prostate tissue specimens to investigate the spatial distribution of a wide variety of small metabolites, carbohydrates, and lipids. In contrast to several previous studies, our method included Krebs cycle intermediates (m/z <200), which we found to be highly informative in distinguishing cancer from benign tissue. Malignant prostate cells showed marked metabolic derangements compared with their benign counterparts. Using the "Least abs. shrinkage and selection operator" (Lasso), we analyzed all metabolites from the DESI-MS data and identified parsimonious sets of metabolic profiles for distinguishing between cancer and normal tissue. In an independent set of samples, we could use these models to classify prostate cancer from benign specimens with nearly 90% accuracy per patient. Based on previous work in prostate cancer showing that glucose levels are high while citrate is low, we found that measurement of the glucose/citrate ion signal ratio accurately predicted cancer when this ratio exceeds 1.0 and normal prostate when the ratio is less than 0.5. After brief tissue prepn., the glucose/citrate ratio can be recorded on a tissue sample in 1 min or less, which is in sharp contrast to the 20 min or more required by histopathol. examn. of frozen tissue specimens.
    25. 25
      Ucal, Y.; Durer, Z. A.; Atak, H.; Kadioglu, E.; Sahin, B.; Coskun, A.; Baykal, A. T.; Ozpinar, A. Clinical applications of MALDI imaging technologies in cancer and neurodegenerative diseases. Biochim. Biophys. Acta, Proteins Proteomics 2017, 1865 (7), 795– 816,  DOI: 10.1016/j.bbapap.2017.01.005
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      Clinical applications of MALDI imaging technologies in cancer and neurodegenerative diseases
      Ucal, Yasemin; Durer, Zeynep Aslihan; Atak, Hakan; Kadioglu, Elif; Sahin, Betul; Coskun, Abdurrahman; Baykal, Ahmet Tarik; Ozpinar, Aysel
      Biochimica et Biophysica Acta, Proteins and Proteomics (2017), 1865 (7), 795-816CODEN: BBAPBW; ISSN:1570-9639. (Elsevier B.V.)
      A review. Matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) imaging mass spectrometry (IMS) enables localization of analytes of interest along with histol. More specifically, MALDI-IMS identifies the distributions of proteins, peptides, small mols., lipids, and drugs and their metabolites in tissues, with high spatial resoln. This unique capacity to directly analyze tissue samples without the need for lengthy sample prepn. reduces tech. variability and renders MALDI-IMS ideal for the identification of potential diagnostic and prognostic biomarkers and disease gradation. MALDI-IMS has evolved rapidly over the last decade and has been successfully used in both medical and basic research by scientists worldwide. In this review, we explore the clin. applications of MALDI-IMS, focusing on the major cancer types and neurodegenerative diseases. In particular, we re-emphasize the diagnostic potential of IMS and the challenges that must be confronted when conducting MALDI-IMS in clin. settings. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.

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    • Abstract

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      Figure 1

      Figure 1. Portrayal ranges of different ionization techniques in the discovery of biomarkers of various molecular weights and polarity.

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      Figure 2

      Figure 2. Schematic overview of the workflow in clinical diagnosis based on mass spectrometry (MALDI-MS or LC-ESI-MS).

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      Figure 3

      Figure 3. Schematic diagrams of (a) desorption electrospray ionization mass spectrometry (DESI-MS), (b) paper spray ionization mass spectrometry (PSI-MS), (c) touch spray ionization mass spectrometry (TSI-MS), (d) extractive electrospray ionization mass spectrometry (EESI-MS), (e) rapid evaporative ionization mass spectrometry (REIMS) or iKnife, (f) MassSpec Pen, (g) direct analysis in real-time mass spectrometry (DART-MS), and (h) matrix-assisted laser desorption electrospray ionization mass spectrometry (MALDESI-MS).

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      Figure 4

      Figure 4. (a) H&E of a prostate tissue specimen that contains both normal (black outline) and cancer (red outline) areas. (b) Negative ion mode DESI-MSI of the adjacent section (15 μm thickness) mapping the differential distribution of a phosphatidic acid (m/z 709.4778) and a phosphatidylserine (m/z 788.5409) throughout the tissue (overlaid image in bicolor), distinguishing the areas of cancer and normal. (c) Extracted ion chronograms of glucose and citrate over a line scan of a typical prostate tissue specimen (H&E shown in the inset) that contains both normal (black outline) and cancer (red outline) areas. (24)

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      Shibdas Banerjee

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      Shibdas Banerjee completed his M.Sc in chemistry at the Indian Institute of Technology (IIT), Roorkee, India, in 2008 and Ph.D. in chemistry at the Tata Institute of Fundamental Research (TIFR), Mumbai, India, in 2014. He worked as a postdoctoral research associate in the laboratory of Prof. Richard N. Zare, Stanford University, USA, from 2014 to 2017. He is currently an assistant professor in the Department of Chemistry, Indian Institute of Science Education and Research (IISER), Tirupati, India.

    • References

      This article references 25 other publications.

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        Ferreira, C. R.; Yannell, K. E.; Jarmusch, A. K.; Pirro, V.; Ouyang, Z.; Cooks, R. G. Ambient Ionization Mass Spectrometry for Point-of-Care Diagnostics and Other Clinical Measurements. Clin. Chem. 2016, 62 (1), 99– 110,  DOI: 10.1373/clinchem.2014.237164
        2
        Ambient ionization mass spectrometry for point-of-care diagnostics and other clinical measurements
        Ferreira, Christina R.; Yannell, Karen E.; Jarmusch, Alan K.; Pirro, Valentina; Ouyang, Zheng; Cooks, R. Graham
        Clinical Chemistry (Washington, DC, United States) (2016), 62 (1), 99-110CODEN: CLCHAU; ISSN:0009-9147. (American Association for Clinical Chemistry)
        BACKGROUND: One driving motivation in the development of point-of-care (POC) diagnostics is to conveniently and immediately provide information upon which healthcare decisions can be based, while the patient is on site. Ambient ionization mass spectrometry (MS) allows direct chem. anal. of unmodified and complex biol. samples. This suite of ionization techniques was introduced a decade ago and now includes a no. of techniques, all seeking to minimize or eliminate sample prepn. Such approaches provide new opportunities for POC diagnostics and rapid measurements of exogenous and endogenous mols. (e.g., drugs, proteins, hormones) in small vols. of biol. samples, esp. when coupled with miniature mass spectrometers. CONTENT: Ambient MS-based techniques are applied in diverse fields such as forensics, pharmaceutical development, reaction monitoring, and food anal. Clin. applications of ambient MS are at an early stage but show promise for POC diagnostics. This review provides a brief overview of various ambient ionization techniques providing background, examples of applications, and the current state of translation to clin. practice. The primary focus is on paper spray (PS) ionization, which allows quantification of analytes in complex biofluids. Current developments in the miniaturization of mass spectrometers are discussed. SUMMARY: Ambient ionization MS is an emerging technol. in anal. and clin. chem. With appropriate MS instrumentation and user-friendly interfaces for automated anal., ambient ionization techniques can provide quant. POC measurements. Most significantly, the implementation of PS could improve the quality and lower the cost of POC testing in a variety of clin. settings.
      3. 3
        Zhang, J.; Rector, J.; Lin, J. Q.; Young, J. H.; Sans, M.; Katta, N.; Giese, N.; Yu, W.; Nagi, C.; Suliburk, J.; Liu, J.; Bensussan, A.; DeHoog, R. J.; Garza, K. Y.; Ludolph, B.; Sorace, A. G.; Syed, A.; Zahedivash, A.; Milner, T. E.; Eberlin, L. S. Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system. Sci. Transl. Med. 2017, 9 (406), eaan3968  DOI: 10.1126/scitranslmed.aan3968
        There is no corresponding record for this reference.
      4. 4
        Kostrzewa, M. Application of the MALDI Biotyper to clinical microbiology: progress and potential. Expert Rev. Proteomics 2018, 15 (3), 193– 202,  DOI: 10.1080/14789450.2018.1438193
        4
        Application of the MALDI Biotyper to clinical microbiology: progress and potential
        Kostrzewa, Markus
        Expert Review of Proteomics (2018), 15 (3), 193-202CODEN: ERPXA3; ISSN:1478-9450. (Taylor & Francis Ltd.)
        A review. The introduction of the MALDI Biotyper in labs. substantially changed microbiol. practice, this has been called a revolution. The system accelerated diagnostic while costs were reduced and accuracy was increased. In just a few years MALDI-TOF MS became the first-line identification tool for microorganisms. Ten years after its introduction, more than 2000 MALDI Biotyper systems are installed in labs. which are performing routine diagnostic, and the no. is still increasing.: This article summarises changes in clin. microbiol. introduced by the MALDI Biotyper and its effects, as it has been published in peer reviewed articles found in PubMed. Further, the potential of novel developments to increase the value of the system is described.: The MALDI Biotyper has significantly improved clin. microbiol. in the area of microorganism identification. Now new developments and applications, e.g. for typing and resistance testing, might further increase its value in clin. microbiol. The systems might get the central diagnostic analyzer which is getting integrated into the widely automated microbiol. labs. of the future.
      5. 5
        Ombrone, D.; Giocaliere, E.; Forni, G.; Malvagia, S.; la Marca, G. Expanded newborn screening by mass spectrometry: New tests, future perspectives. Mass Spectrom. Rev. 2016, 35 (1), 71– 84,  DOI: 10.1002/mas.21463
        5
        Expanded newborn screening by mass spectrometry: New tests, future perspectives
        Ombrone, Daniela; Giocaliere, Elisa; Forni, Giulia; Malvagia, Sabrina; la Marca, Giancarlo
        Mass Spectrometry Reviews (2016), 35 (1), 71-84CODEN: MSRVD3; ISSN:0277-7037. (John Wiley & Sons, Inc.)
        Tandem mass spectrometry (MS/MS) has become a leading technol. used in clin. chem. and has shown to be particularly sensitive and specific when used in newborn screening (NBS) tests. The success of tandem mass spectrometry is due to important advances in hardware, software and clin. applications during the last 25 years. MS/MS permits a very rapid measurement of many metabolites in different biol. specimens by using filter paper spots or directly on biol. fluids. Its use in NBS give us the chance to identify possible treatable metabolic disorders even when asymptomatic and the benefits gained by this type of screening is now recognized worldwide. Today the use of MS/MS for second-tier tests and confirmatory testing is promising esp. in the early detection of new disorders such as some lysosomal storage disorders, ADA and PNP SCIDs, X-adrenoleucodistrophy (X-ALD), Wilson disease, guanidinoacetate methyltransferase deficiency (GAMT), and Duchenne muscular dystrophy. The new challenge for the future will be reducing the false pos. rate by using second-tier tests, avoiding false neg. results by using new specific biomarkers and introducing new treatable disorders in NBS programs.
      6. 6
        Jannetto, P. J. Chapter 8 - Therapeutic drug monitoring using mass spectrometry. In Mass Spectrometry for the Clinical Laboratory; Nair, H., Clarke, W., Eds.; Academic Press: San Diego, 2017; pp 165– 179.
        There is no corresponding record for this reference.
      7. 7
        Volmer, D. A.; Mendes, L. R. B. C.; Stokes, C. S. Analysis of vitamin D metabolic markers by mass spectrometry: Current techniques, limitations of the “gold standard” method, and anticipated future directions. Mass Spectrom. Rev. 2015, 34 (1), 2– 23,  DOI: 10.1002/mas.21408
        7
        Analysis of vitamin D metabolic markers by mass spectrometry: Current techniques, limitations of the "gold standard" method, and anticipated future directions
        Volmer, Dietrich A.; Mendes, Luana R. B. C.; Stokes, Caroline S.
        Mass Spectrometry Reviews (2015), 34 (1), 2-23CODEN: MSRVD3; ISSN:0277-7037. (John Wiley & Sons, Inc.)
        A review. Vitamin D compds. belong to a group of secosteroids, which occur naturally as vitamin D3 in mammals and D2 in plants. Vitamin D is vital for bone health but recent studies showed a much wider role in the pathologies of diseases such as diabetes, cancer, autoimmune, neurodegenerative, mental and cardiovascular diseases. Photosynthesis of vitamin D in the human skin and subsequent hepatic and renal metab. generate a wide range of transformation products occurring over a large dynamic range spanning from picomolar to nanomolar levels. This necessitates selective and sensitive anal. methods to quant. capture these low concn. levels in relevant tissues such as blood. Ideally, vitamin D assessment would be performed using a universal and standardized anal. method available to clin. labs. that provides reliable and accurate quant. results for all relevant vitamin D metabolites with sufficiently high throughput. At present, LC-MS/MS assays are the most promising techniques for vitamin D anal. The present review focuses on developments in mass spectrometry methodologies of the past 12 years. It will highlight detrimental influences of the biol. matrix, epimer contributions, pitfalls of specific mass spectrometry data acquisition routines (in particular multiple reaction monitoring, MRM), influence of ionization source, derivatization reactions, inter-lab. comparisons on precision, accuracy, and application range of vitamin D metabolites. © 2013 Wiley Periodicals, Inc. Mass Spec Rev 34: 2-23, 2015.
      8. 8
        Perakakis, N.; Yazdani, A.; Karniadakis, G. E.; Mantzoros, C. Omics, big data and machine learning as tools to propel understanding of biological mechanisms and to discover novel diagnostics and therapeutics. Metab., Clin. Exp. 2018, 87, A1– A9,  DOI: 10.1016/j.metabol.2018.08.002
        8
        Omics, big data and machine learning as tools to propel understanding of biological mechanisms and to discover novel diagnostics and therapeutics
        Perakakis, Nikolaos; Yazdani, Alireza; Karniadakis, George E.; Mantzoros, Christos
        Metabolism, Clinical and Experimental (2018), 87 (), A1-A9CODEN: METAAJ; ISSN:0026-0495. (Elsevier)
        A review summarizing the most important "omics" procedures and describe the current challenges related to their use. Addnl., we describe the novel methods of data-mining and machine learning anal., and particularly, how they can be used in a hierarchical manner to produce robust results for medicine from big data.
      9. 9
        Banerjee, S. Ambient ionization mass spectrometry imaging for disease diagnosis: Excitements and challenges. J. Biosci. 2018, 43 (4), 731– 738,  DOI: 10.1007/s12038-018-9785-y
        9
        Ambient ionization mass spectrometry imaging for disease diagnosis: Excitements and challenges
        Banerjee, Shibdas
        Journal of Biosciences (New Delhi, India) (2018), 43 (4), 731-738CODEN: JOBSDN; ISSN:0250-5991. (Springer (India) Private Ltd.)
        A review. Tissue anal. in histol. is extremely important and also considered to be a gold std. to diagnose and prognosticate several diseases including cancer. Intraoperative evaluation of surgical margin of tumor also relies on frozen section histopathol., which is time consuming, challenging and often subjective. Recent development in the ambient ionization mass spectrometry imaging (MSI) technique has enabled us to simultaneously visualize hundreds to thousands of mols. (ion images) in the biopsy specimen, which are strikingly different and more powerful than the single optical tissue image anal. in conventional histopathol. This paper will highlight the emergence of the desorption electrospray ionization MSI (DESI-MSI) technique, which is label-free, requires minimal or no sample prepn. and operates under ambient conditions. DESI-MSI can record ion images of lipid/metabolite distributions on biopsy specimens, providing a wealth of diagnostic information based on differential distributions of these mol. species in healthy and unhealthy tissues. Remarkable success of this technol. in rapidly evaluating the cancer margin intraoperatively with very high accuracy also promises to bring this imaging technique from bench to bedside.
      10. 10
        Li, L.-H.; Hsieh, H.-Y.; Hsu, C.-C. Clinical Application of Ambient Ionization Mass Spectrometry. Mass Spectrom. 2017, 6 (2), S0060– S0060,  DOI: 10.5702/massspectrometry.S0060
        10
        Clinical application of ambient ionization mass spectrometry
        Li, Li-Hua; Hsieh, Hua-Yi; Hsu, Cheng-Chih
        Mass Spectrometry (2017), 6 (2Spec.Iss.), S0060/1-S0060/12CODEN: MSAPG5; ISSN:2187-137X. (Mass Spectrometry Society of Japan)
        Ambient ionization allows mass spectrometry anal. directly on the sample surface under atm. pressure with almost zero sample pretreatment. Since the development of desorption electrospray ionization (DESI) in 2004, many other ambient ionization techniques were developed. Due to their simplicity and low operation cost, rapid and on-site clin. mass spectrometry anal. becomes real. In this review, we will highlight some of the most widely used ambient ionization mass spectrometry approaches and their applications in clin. study.
      11. 11
        Takáts, Z.; Wiseman, J. M.; Gologan, B.; Cooks, R. G. Mass Spectrometry Sampling Under Ambient Conditions with Desorption Electrospray Ionization. Science 2004, 306 (5695), 471– 473,  DOI: 10.1126/science.1104404
        11
        Mass Spectrometry Sampling Under Ambient Conditions with Desorption Electrospray Ionization
        Takats, Zoltan; Wiseman, Justin M.; Gologan, Bogdan; Cooks, R. Graham
        Science (Washington, DC, United States) (2004), 306 (5695), 471-473CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
        A new method of desorption ionization is described and applied to the ionization of various compds., including peptides and proteins present on metal, polymer, and mineral surfaces. Desorption electrospray ionization (DESI) is carried out by directing electrosprayed charged droplets and ions of solvent onto the surface to be analyzed. The impact of the charged particles on the surface produces gaseous ions of material originally present on the surface. The resulting mass spectra are similar to normal ESI mass spectra in that they show mainly singly or multiply charged mol. ions of the analytes. The DESI phenomenon was obsd. both in the case of conductive and insulator surfaces and for compds. ranging from nonpolar small mols. such as lycopene, the alkaloid coniceine, and small drugs, through polar compds. such as peptides and proteins. Changes in the soln. that is sprayed can be used to selectively ionize particular compds., including those in biol. matrixes. In vivo anal. is demonstrated.
      12. 12
        Eberlin, L. S.; Dill, A. L.; Golby, A. J.; Ligon, K. L.; Wiseman, J. M.; Cooks, R. G.; Agar, N. Y. R. Discrimination of Human Astrocytoma Subtypes by Lipid Analysis Using Desorption Electrospray Ionization Imaging Mass Spectrometry. Angew. Chem., Int. Ed. 2010, 49 (34), 5953– 5956,  DOI: 10.1002/anie.201001452
        12
        Discrimination of Human Astrocytoma Subtypes by Lipid Analysis Using Desorption Electrospray Ionization Imaging Mass Spectrometry
        Eberlin, Livia S.; Dill, Allison L.; Golby, Alexandra J.; Ligon, Keith L.; Wiseman, Justin M.; Cooks, R. Graham; Agar, Nathalie Y. R.
        Angewandte Chemie, International Edition (2010), 49 (34), 5953-5956, S5953/1-S5953/12CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
        This study was to use desorption electrospray ionization imaging mass spectrometry (DESI-MS) to analyze and characterize the lipid profiles of different grades of human astrocytomas.
      13. 13
        Eberlin, L. S.; Ferreira, C. R.; Dill, A. L.; Ifa, D. R.; Cooks, R. G. Desorption electrospray ionization mass spectrometry for lipid characterization and biological tissue imaging. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2011, 1811 (11), 946– 960,  DOI: 10.1016/j.bbalip.2011.05.006
        13
        Desorption electrospray ionization mass spectrometry for lipid characterization and biological tissue imaging
        Eberlin, Livia S.; Ferreira, Christina R.; Dill, Allison L.; Ifa, Demian R.; Cooks, R. Graham
        Biochimica et Biophysica Acta, Molecular and Cell Biology of Lipids (2011), 1811 (11), 946-960CODEN: BBMLFG; ISSN:1388-1981. (Elsevier B. V.)
        A review. Desorption electrospray ionization mass spectrometry (DESI-MS) imaging of biol. samples allows untargeted anal. and structural characterization of lipids ionized from the near-surface region of a sample under ambient conditions. DESI is a powerful and sensitive MS ionization method for 2D and 3D imaging of lipids from direct and unmodified complex biol. samples. This review describes the strengths and limitations of DESI-MS for lipid characterization and imaging together with the tech. workflow and a survey of applications. Included are discussions of lipid mapping and biomarker discovery as well as a perspective on the future of DESI imaging.
      14. 14
        Liu, J.; Wang, H.; Manicke, N. E.; Lin, J.-M.; Cooks, R. G.; Ouyang, Z. Development, Characterization, and Application of Paper Spray Ionization. Anal. Chem. 2010, 82 (6), 2463– 2471,  DOI: 10.1021/ac902854g
        14
        Development, Characterization, and Application of Paper Spray Ionization
        Liu, Jiangjiang; Wang, He; Manicke, Nicholas E.; Lin, Jin-Ming; Cooks, R. Graham; Ouyang, Zheng
        Analytical Chemistry (Washington, DC, United States) (2010), 82 (6), 2463-2471CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
        Paper spray is developed as a direct sampling ionization method for mass spectrometric anal. of complex mixts. Ions of analyte are generated by applying a high voltage to a paper triangle wetted with a small vol. (<10 μL) of soln. Samples can be preloaded onto the paper, added with the wetting soln., or transferred from surfaces using the paper as a wipe. It is demonstrated that paper spray is applicable to the anal. of a wide variety of compds., including small org. compds., peptides, and proteins. Procedures are developed for anal. of dried biofluid spots and applied to therapeutic drug monitoring with whole blood samples and to illicit drug detection in raw urine samples. Limits of detection of 50 ng/mL (or 20 pg abs.) are achieved for atenolol in bovine blood. The combination of sample collection from surfaces and paper spray ionization also enables fast chem. screening at high sensitivity, for example 100 pg of heroin distributed on a surface and agrochems. on fruit peels are detectable. Online derivatization with a preloaded reagent is demonstrated for anal. of cholesterol in human serum. The combination of paper spray with miniature mass spectrometers offers a powerful impetus to wide application of mass spectrometry in nonlab. environments.
      15. 15
        Chiang, S.; Zhang, W.; Ouyang, Z. Paper spray ionization mass spectrometry: recent advances and clinical applications. Expert Rev. Proteomics 2018, 15 (10), 781– 789,  DOI: 10.1080/14789450.2018.1525295
        15
        Paper spray ionization mass spectrometry: recent advances and clinical applications
        Chiang, Spencer; Zhang, Wenpeng; Ouyang, Zheng
        Expert Review of Proteomics (2018), 15 (10), 781-789CODEN: ERPXA3; ISSN:1478-9450. (Taylor & Francis Ltd.)
        A review. Introduction: Paper spray mass spectrometry has provided a rapid, quant. ambient ionization method for xenobiotic and biomol. anal. As an alternative to traditional sample prepn. and chromatog., paper spray demonstrates the sampling ionization of a wide range of mols. and significant sensitivity from complex biofluids. The amenability of paper spray with dried blood spots and other sampling types shows strong potential for rapid, point-of-care (POC) anal. without time-consuming sepn. procedures. Areas covered: This special report summarizes the current state and advances in paper spray mass spectrometry that relate to its applicability for clin. anal. It also provides our perspectives on the future development of paper spray mass spectrometry and its potential roles in clin. settings. Expert commentary: Paper spray has provided the fundamental aspects of ambient ionization needed for implementation at the POC. With further clin. management and standardization, paper spray has the potential to replace traditional complex anal. procedure for rapid quant. detection of illicit drugs, therapeutic drugs and metabolites. Surface and substrate modifications also offer significant improvement in desorption and ionization efficiencies, resulting in enhanced sensitivity. Comprehensive anal. of metabolites and lipids will further extend the implementation of paper spray ionization mass spectrometry into clin. applications.
      16. 16
        Kerian, K. S.; Jarmusch, A. K.; Cooks, R. G. Touch spray mass spectrometry for in situ analysis of complex samples. Analyst 2014, 139 (11), 2714– 2720,  DOI: 10.1039/C4AN00548A
        16
        Touch spray mass spectrometry for in situ analysis of complex samples
        Kerian, Kevin S.; Jarmusch, Alan K.; Cooks, R. Graham
        Analyst (Cambridge, United Kingdom) (2014), 139 (11), 2714-2720CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)
        Touch spray, a spray-based ambient in situ ionization method, uses a small probe, e.g. a teasing needle to pick up sample and the application of voltage and solvent to cause field-induced droplet emission. Compds. extd. from the microsample are incorporated into the sprayed micro droplets. Performance tests include disease state of tissue, microorganism identification, and therapeutic drug quantitation. Chem. derivatization was performed simultaneously with ionization.
      17. 17
        Ifa, D. R.; Eberlin, L. S. Ambient Ionization Mass Spectrometry for Cancer Diagnosis and Surgical Margin Evaluation. Clin. Chem. 2016, 62 (1), 111– 123,  DOI: 10.1373/clinchem.2014.237172
        17
        Ambient ionization mass spectrometry for cancer diagnosis and surgical margin evaluation
        Ifa, Demian R.; Eberlin, Livia S.
        Clinical Chemistry (Washington, DC, United States) (2016), 62 (1), 111-123CODEN: CLCHAU; ISSN:0009-9147. (American Association for Clinical Chemistry)
        BACKGROUND: There is a clin. need for new technologies that would enable rapid disease diagnosis based on diagnostic mol. signatures. Ambient ionization mass spectrometry has revolutionized the means by which mol. information can be obtained from tissue samples in real time and with minimal sample pretreatment. New developments in ambient ionization techniques applied to clin. research suggest that ambient ionization mass spectrometry will soon become a routine medical tool for tissue diagnosis. CONTENT: This review summarizes the main developments in ambient ionization techniques applied to tissue anal., with focus on desorption electrospray ionization mass spectrometry, probe electrospray ionization, touch spray, and rapid evaporative ionization mass spectrometry. We describe their applications to human cancer research and surgical margin evaluation, highlighting integrated approaches tested for ex vivo and in vivo human cancer tissue anal. We also discuss the challenges for clin. implementation of these tools and offer perspectives on the future of the field. SUMMARY: A variety of studies have showcased the value of ambient ionization mass spectrometry for rapid and accurate cancer diagnosis. Small mols. have been identified as potential diagnostic biomarkers, including metabolites, fatty acids, and glycerophospholipids. Statistical anal. allows tissue discrimination with high accuracy rates (>95%) being common. This young field has challenges to overcome before it is ready to be broadly accepted as a medical tool for cancer diagnosis. Growing research in new, integrated ambient ionization mass spectrometry technologies and the ongoing improvements in the existing tools make this field very promising for future translation into the clinic.
      18. 18
        Gu, H.; Xu, N.; Chen, H. Direct analysis of biological samples using extractive electrospray ionization mass spectrometry (EESI-MS). Anal. Bioanal. Chem. 2012, 403 (8), 2145– 2153,  DOI: 10.1007/s00216-012-5874-1
        18
        Direct analysis of biological samples using extractive electrospray ionization mass spectrometry (EESI-MS)
        Gu, Haiwei; Xu, Ning; Chen, Huanwen
        Analytical and Bioanalytical Chemistry (2012), 403 (8), 2145-2153CODEN: ABCNBP; ISSN:1618-2642. (Springer)
        Mass spectrometry (MS) is one of the most widely used techniques for the anal. of biol. samples. In the past decade, a novel improvement in MS was the invention of ambient ionization which stands out owing to its unique capability of direct anal. of complex samples with no or minimal pretreatment. In this review, extractive electrospray ionization (EESI), a representative ambient ionization technique, is introduced focusing on its mechanism, instrumentation, and applications in biol. anal. EESI uses a traditional ESI channel to produce primary ions which subsequently ionize neutral chems. from the sample introduction channel through an online extn. process. When analyzing biol. samples, EESI has advantages of rapid anal., high matrix tolerance, and the ability to perform in vivo anal. According to previous studies, EESI is able to directly analyze various chems. in complex biol. specimens in liq., gas, and solid states. EESI can provide a sensitive and selective measurement of biol. samples for both qual. and quant. purposes. Therefore, it is anticipated that EESI will have promising applications, esp. in fields which require the fast and/or in vivo anal. of biol. samples with complicated matrixes.
      19. 19
        Balog, J.; Sasi-Szabó, L.; Kinross, J.; Lewis, M. R.; Muirhead, L. J.; Veselkov, K.; Mirnezami, R.; Dezso, B.; Damjanovich, L.; Darzi, A.; Nicholson, J. K.; Takáts, Z. Intraoperative Tissue Identification Using Rapid Evaporative Ionization Mass Spectrometry. Sci. Transl. Med. 2013, 5 (194), 194ra93– 194ra93,  DOI: 10.1126/scitranslmed.3005623
        There is no corresponding record for this reference.
      20. 20
        Takats, Z.; Denes, J.; Kinross, J. Identifying the margin: a new method to distinguish between cancerous and noncancerous tissue during surgery. Future Oncol. 2012, 8 (2), 113– 116,  DOI: 10.2217/fon.11.151
        20
        Identifying the margin: a new method to distinguish between cancerous and noncancerous tissue during surgery
        Takats Zoltan; Denes Julia; Kinross James
        Future oncology (London, England) (2012), 8 (2), 113-6 ISSN:.
        There is no expanded citation for this reference.
      21. 21
        Banerjee, S.; Manna, S. K. Assessment of Metabolic Signature for Cancer Diagnosis Using Desorption Electrospray Ionization Mass Spectrometric Imaging. In Cancer Metabolism: Methods and Protocols; Haznadar, M., Ed.; Springer New York: New York, NY, 2019; pp 275– 297.
        There is no corresponding record for this reference.
      22. 22
        Li, Y. Application of DART-MS in Clinical and Pharmacological Analysis. In Direct Analysis in Real Time Mass Spectrometry; Dong, Y., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: 2017; pp 223– 240.
        There is no corresponding record for this reference.
      23. 23
        Barry, J. A.; Robichaud, G.; Bokhart, M. T.; Thompson, C.; Sykes, C.; Kashuba, A. D. M.; Muddiman, D. C. Mapping antiretroviral drugs in tissue by IR-MALDESI MSI coupled to the Q Exactive and comparison with LC-MS/MS SRM assay. J. Am. Soc. Mass Spectrom. 2014, 25 (12), 2038– 2047,  DOI: 10.1007/s13361-014-0884-1
        23
        Mapping Antiretroviral Drugs in Tissue by IR-MALDESI MSI Coupled to the Q Exactive and Comparison with LC-MS/MS SRM Assay
        Barry, Jeremy A.; Robichaud, Guillaume; Bokhart, Mark T.; Thompson, Corbin; Sykes, Craig; Kashuba, Angela D. M.; Muddiman, David C.
        Journal of the American Society for Mass Spectrometry (2014), 25 (12), 2038-2047CODEN: JAMSEF; ISSN:1044-0305. (Springer)
        This work describes the coupling of the IR-MALDESI imaging source with the Q Exactive mass spectrometer. IR-MALDESI MSI was used to elucidate the spatial distribution of several HIV drugs in cervical tissues that had been incubated in either a low or high concn. Serial sections of those analyzed by IR-MALDESI MSI were homogenized and analyzed by LC-MS/MS to quantify the amt. of each drug present in the tissue. By comparing the two techniques, an agreement between the av. intensities from the imaging expt. and the abs. quantities for each drug was obsd. This correlation between these two techniques serves as a prerequisite to quant. IR-MALDESI MSI. In addn., a targeted MS2 imaging expt. was also conducted to demonstrate the capabilities of the Q Exactive and to highlight the added selectivity that can be obtained with SRM or MRM imaging expts.
      24. 24
        Banerjee, S.; Zare, R. N.; Tibshirani, R. J.; Kunder, C. A.; Nolley, R.; Fan, R.; Brooks, J. D.; Sonn, G. A. Diagnosis of prostate cancer by desorption electrospray ionization mass spectrometric imaging of small metabolites and lipids. Proc. Natl. Acad. Sci. U. S. A. 2017, 114 (13), 3334– 3339,  DOI: 10.1073/pnas.1700677114
        24
        Diagnosis of prostate cancer by desorption electrospray ionization mass spectrometric imaging of small metabolites and lipids
        Banerjee, Shibdas; Zare, Richard N.; Tibshirani, Robert J.; Kunder, Christian A.; Nolley, Rosalie; Fan, Richard; Brooks, James D.; Sonn, Geoffrey A.
        Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (13), 3334-3339CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
        Accurate identification of prostate cancer in frozen sections at the time of surgery can be challenging, limiting the surgeon's ability to best det. resection margins during prostatectomy. We performed desorption electrospray ionization mass spectrometry imaging (DESI-MSI) on 54 banked human cancerous and normal prostate tissue specimens to investigate the spatial distribution of a wide variety of small metabolites, carbohydrates, and lipids. In contrast to several previous studies, our method included Krebs cycle intermediates (m/z <200), which we found to be highly informative in distinguishing cancer from benign tissue. Malignant prostate cells showed marked metabolic derangements compared with their benign counterparts. Using the "Least abs. shrinkage and selection operator" (Lasso), we analyzed all metabolites from the DESI-MS data and identified parsimonious sets of metabolic profiles for distinguishing between cancer and normal tissue. In an independent set of samples, we could use these models to classify prostate cancer from benign specimens with nearly 90% accuracy per patient. Based on previous work in prostate cancer showing that glucose levels are high while citrate is low, we found that measurement of the glucose/citrate ion signal ratio accurately predicted cancer when this ratio exceeds 1.0 and normal prostate when the ratio is less than 0.5. After brief tissue prepn., the glucose/citrate ratio can be recorded on a tissue sample in 1 min or less, which is in sharp contrast to the 20 min or more required by histopathol. examn. of frozen tissue specimens.
      25. 25
        Ucal, Y.; Durer, Z. A.; Atak, H.; Kadioglu, E.; Sahin, B.; Coskun, A.; Baykal, A. T.; Ozpinar, A. Clinical applications of MALDI imaging technologies in cancer and neurodegenerative diseases. Biochim. Biophys. Acta, Proteins Proteomics 2017, 1865 (7), 795– 816,  DOI: 10.1016/j.bbapap.2017.01.005
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        Clinical applications of MALDI imaging technologies in cancer and neurodegenerative diseases
        Ucal, Yasemin; Durer, Zeynep Aslihan; Atak, Hakan; Kadioglu, Elif; Sahin, Betul; Coskun, Abdurrahman; Baykal, Ahmet Tarik; Ozpinar, Aysel
        Biochimica et Biophysica Acta, Proteins and Proteomics (2017), 1865 (7), 795-816CODEN: BBAPBW; ISSN:1570-9639. (Elsevier B.V.)
        A review. Matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) imaging mass spectrometry (IMS) enables localization of analytes of interest along with histol. More specifically, MALDI-IMS identifies the distributions of proteins, peptides, small mols., lipids, and drugs and their metabolites in tissues, with high spatial resoln. This unique capacity to directly analyze tissue samples without the need for lengthy sample prepn. reduces tech. variability and renders MALDI-IMS ideal for the identification of potential diagnostic and prognostic biomarkers and disease gradation. MALDI-IMS has evolved rapidly over the last decade and has been successfully used in both medical and basic research by scientists worldwide. In this review, we explore the clin. applications of MALDI-IMS, focusing on the major cancer types and neurodegenerative diseases. In particular, we re-emphasize the diagnostic potential of IMS and the challenges that must be confronted when conducting MALDI-IMS in clin. settings. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.