Review Article

Prostate cancer diagnosis and characterization with mass spectrometry imaging

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Published online:

Abstract

Background

Prostate cancer (PCa), the most common cancer and second leading cause of cancer death in American men, presents the clinical challenge of distinguishing between indolent and aggressive tumors for proper treatment. PCa presents significant alterations in metabolic pathways that can potentially be measured using techniques like mass spectrometry (MS) or MS imaging (MSI) and used to characterize PCa aggressiveness. MS quantifies metabolomic, proteomic, and lipidomic profiles of biological systems that can be further visualized for their spatial distributions through MSI.

Methods

PubMed was queried for all publications relating to MS and MSI in human PCa from April 2007 to April 2017. With the goal of reviewing the utility of MSI in diagnosis and prognostication of human PCa, MSI articles that reported investigations of PCa-specific metabolites or metabolites indicating PCa aggressiveness were selected for inclusion. Articles were included that covered MS and MSI principles, limitations, and applications in PCa.

Results

We identified nine key studies on MSI in intact human prostate tissue specimens that determined metabolites which could either differentiate between benign and malignant prostate tissue or indicate PCa aggressiveness. These MSI-detected biomarkers show promise in reliably identifying PCa and determining disease aggressiveness.

Conclusions

MSI represents an innovative technique with the ability to interrogate cancer biomarkers in relation to tissue pathologies and investigate tumor aggressiveness. We propose MSI as a powerful adjuvant histopathology imaging tool for prostate tissue evaluations, where clinical translation of this ex vivo technique could make possible the use of MSI for personalized medicine in diagnosis and prognosis of PCa. Moreover, the knowledge provided from this technique can majorly contribute to the understanding of molecular pathogenesis of PCa and other malignant diseases.

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References

  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. Cancer J Clin. 2017;67:7–30.

  2. 2.

    Institute NC. SEER Stat Fact Sheets: Prostate. Bethesda, MD: National Cancer Institute; 2011.

  3. 3.

    Lu-Yao GL, Albertsen PC, Moore DF, Shih W, Lin Y, DiPaola RS, et al. Outcomes of localized prostate cancer following conservative management. JAMA. 2009;302:1202–09

  4. 4.

    Albertsen PC, Moore DF, Shih W, Lin Y, Li H, Lu-Yao GL. Impact of comorbidity on survival among men with localized prostate cancer. J Clin Oncol. 2011;29:1335–41.

  5. 5.

    Draisma G, Boer R, Otto SJ, van der Cruijsen IW, Damhuis RA, Schroder FH, et al. Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst. 2003;95:868–78

  6. 6.

    Andriole GL, Crawford ED, Grubb RL,III, Buys SS, Chia D, Church TR, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:1310–19

  7. 7.

    Welch HG, Albertsen PC. Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening: 1986–2005. J Natl Cancer Inst. 2009;101:1325–29.

  8. 8.

    Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst 2010;102:605–13.

  9. 9.

    Zelefsky M, Eastham J, Sartor A. Cancer of the prostate. In: DeVita VJ, Lawrence T, Rosenberg S, editors. Cancer: principles and practice of oncology. 9th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011. p. 1220–71.

  10. 10.

    Chan TY, Partin AW, Walsh PC, Epstein JI. Prognostic significance of Gleason score 3 + 4 versus Gleason score 4+3 tumor at radical prostatectomy. Urology. 2000;56:823–27.

  11. 11.

    Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, Humphrey PA. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading Patterns and Proposal for a New Grading System. Am J Surg Pathol. 2016;40:244–52.

  12. 12.

    Kerian KS, Jarmusch AK, Pirro V, Koch MO, Masterson TA, Cheng L, et al. Differentiation of prostate cancer from normal tissue in radical prostatectomy specimens by desorption electrospray ionization and touch spray ionization mass spectrometry. Analyst. 2015;140:1090–98.

  13. 13.

    Garbis SD, Tyritzis SI, Roumeliotis T, Zerefos P, Giannopoulou EG, Vlahou A, et al. Search for potential markers for prostate cancer diagnosis, prognosis and treatment in clinical tissue specimens using amine-specific isobaric tagging (iTRAQ) with two-dimensional liquid chromatography and tandem mass spectrometry. J Proteome Res. 2008;7:3146–58.

  14. 14.

    Sarafanov AG, Todorov TI, Kajdacsy-Balla A, Gray MA, Macias V, Centeno JA. Analysis of iron, zinc, selenium and cadmium in paraffin-embedded prostate tissue specimens using inductively coupled plasma mass-spectrometry. J Trace Elem Med Biol. 2008;22:305–14.

  15. 15.

    McDunn JE, Li Z, Adam KP, Neri BP, Wolfert RL, Milburn MV, et al. Metabolomic signatures of aggressive prostate cancer. Prostate 2013;73:1547–60.

  16. 16.

    Saylor PJ, Karoly ED, Smith MR. Prospective study of changes in the metabolomic profiles of men during their first three months of androgen deprivation therapy for prostate cancer. Clin Cancer Res. 2012;18:3677–85.

  17. 17.

    Jung K, Reszka R, Kamlage B, Bethan B, Stephan C, Lein M, et al. Tissue metabolite profiling identifies differentiating and prognostic biomarkers for prostate carcinoma. Int J Cancer. 2013;133:2914–24.

  18. 18.

    Kami K, Fujimori T, Sato H, Sato M, Yamamoto H, Ohashi Y, et al. Metabolomic profiling of lung and prostate tumor tissues by capillary electrophoresis time-of-flight mass spectrometry. Metabolomics. 2013;9:444–53.

  19. 19.

    Fenn JB, Mann M, Meng CK, Wong SF, Whitehouse CM. Electrospray ionization for mass spectrometry of large biomolecules. Science. 1989;246:64–71.

  20. 20.

    Karas M, Bachmann D, Hillenkamp F. Influence of the wavelength in high-irradiance ultraviolet laser desorption mass spectrometry of organic molecules. Anal Chem. 1985;57:2935–39.

  21. 21.

    Tanaka K, Waki H, Ido Y, Akita S, Yoshida Y, Yoshida T, et al. Protein and polymer analyses up to m/z 100 000 by laser ionization time‐of‐flight mass spectrometry. Rapid Commun Mass Spectrom. 1988;2:151–53.

  22. 22.

    Chernushevich IV, Loboda AV, Thomson BA. An introduction to quadrupole–time‐of‐flight mass spectrometry. J Mass Spectrom. 2001;36:849–65.

  23. 23.

    Yost R, Enke C. Selected ion fragmentation with a tandem quadrupole mass spectrometer. J Am Chem Soc. 1978;100:2274–75.

  24. 24.

    Shevchenko A, Loboda A, Shevchenko A, Ens W, Standing KG. MALDI quadrupole time-of-flight mass spectrometry: a powerful tool for proteomic research. Anal Chem. 2000;72:2132–41.

  25. 25.

    Marshall AG, Hendrickson CL, Jackson GS. Fourier transform ion cyclotron resonance mass spectrometry: a primer. Mass Spectrom Rev. 1998;17:1–35.

  26. 26.

    Lodi A, Ronen SM. Magnetic resonance spectroscopy detectable metabolomic fingerprint of response to antineoplastic treatment. PLoS ONE. 2011;6:e26155.

  27. 27.

    Teahan O, Bevan CL, Waxman J, Keun HC. Metabolic signatures of malignant progression in prostate epithelial cells. Int J Biochem Cell Biol. 2011;43:1002–09.

  28. 28.

    Burch TC, Isaac G, Booher CL, Rhim JS, Rainville P, Langridge J, et al. Comparative metabolomic and lipidomic analysis of phenotype stratified prostate cells. PLoS ONE. 2015;10:e0134206.

  29. 29.

    Teichert F, Verschoyle RD, Greaves P, Edwards RE, Teahan O, Jones DJ, et al. Metabolic profiling of transgenic adenocarcinoma of mouse prostate (TRAMP) tissue by 1H-NMR analysis: evidence for unusual phospholipid metabolism. Prostate. 2008;68:1035–47.

  30. 30.

    Raina K, Ravichandran K, Rajamanickam S, Huber KM, Serkova NJ, Agarwal R. Inositol hexaphosphate inhibits tumorgrowth, vascularity, and metabolism in TRAMP mice: a Multiparametric Magnetic Resonance Study. Cancer Prev Res. 2013;6:40–50.

  31. 31.

    Chaurand P, Rahman MA, Hunt T, Mobley JA, Gu G, Latham JC, et al. Monitoring mouse prostate development by profiling and imaging mass spectrometry. Mol Cell Proteomics. 2008;7:411–23.

  32. 32.

    Wu H, Liu T, Ma C, Xue R, Deng C, Zeng H, et al. GC/MS-based metabolomic approach to validate the role of urinary sarcosine and target biomarkers for human prostate cancer by microwave-assisted derivatization. Anal Bioanal Chem. 2011;401:635–46.

  33. 33.

    Fan Y, Murphy TB, Byrne JC, Brennan L, Fitzpatrick JM, Watson RW. Applying random forests to identify biomarker panels in serum 2D-DIGE data for the detection and staging of prostate cancer. J Proteome Res. 2011;10:1361–73.

  34. 34.

    Miyagi Y, Higashiyama M, Gochi A, Akaike M, Ishikawa T, Miura T, et al Plasma free amino acid profiling of five types of cancer patients and its application for early detection. PLoS ONE. 2011;6:e24143.

  35. 35.

    Lokhov PG, Balashova EE, Voskresenskaya AA, Trifonova OP, Maslov DL, Archakov AI. Mass spectrometric signatures of the blood plasma metabolome for disease diagnostics. Biomed Rep. 2016;4:122–26.

  36. 36.

    Giskeodegard GF, Hansen AF, Bertilsson H, Gonzalez SV, Kristiansen KA, Bruheim P, et al. Metabolic markers in blood can separate prostate cancer from benign prostatic hyperplasia. Br J Cancer. 2015;113:1712–19.

  37. 37.

    Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009;457:910–14.

  38. 38.

    Meller S, Meyer HA, Bethan B, Dietrich D, Maldonado SG, Lein M, et al. Integration of tissue metabolomics, transcriptomics and immunohistochemistry reveals ERG- and gleason score-specific metabolomic alterations in prostate cancer. Oncotarget. 2016;7:1421–38.

  39. 39.

    Demichelis F, Fall K, Perner S, Andren O, Schmidt F, Setlur SR, et al. TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene. 2007;26:4596–99.

  40. 40.

    Attard G, Clark J, Ambroisine L, Fisher G, Kovacs G, Flohr P, et al. Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene. 2008;27:253–63.

  41. 41.

    Cacciatore S, Zadra G, Bango C, Penney KL, Tyekucheva S, Yanes O et al. Metabolic profiling in formalin-fixed and paraffin-embedded prostate cancer tissues. Mol Cancer Res. 2017:15:439–47.

  42. 42.

    Shuster JR, Lance RS, Troyer DA. Molecular preservation by extraction and fixation, mPREF: a method for small molecule biomarker analysis and histology on exactly the same tissue. BMC Clin Pathol. 2011;11:14.

  43. 43.

    Cohen LH, Gusev AI. Small molecule analysis by MALDI mass spectrometry. Anal Bioanal Chem. 2002;373:571–86.

  44. 44.

    Franck J, Longuespee R, Wisztorski M, Van Remoortere A, Van Zeijl R, Deelder A, et al. MALDI mass spectrometry imaging of proteins exceeding 30,000 daltons. Med Sci Monitor. 2010;16:Br293–99.

  45. 45.

    Mainini V, Bovo G, Chinello C, Gianazza E, Grasso M, Cattoretti G, et al. Detection of high molecular weight proteins by MALDI imaging mass spectrometry. Mol Biosyst. 2013;9:1101–07.

  46. 46.

    Reyzer ML, Hsieh Y, Ng K, Korfmacher WA, Caprioli RM. Direct analysis of drug candidates in tissue by matrix-assisted laser desorption/ionization mass spectrometry. J Mass Spectrom. 2003;38:1081–92.

  47. 47.

    Svatos A. Mass spectrometric imaging of small molecules. Trends Biotechnol. 2010;28:425–34.

  48. 48.

    van Remoortere A, van Zeijl RJ, van den Oever N, Franck J, Longuespee R, Wisztorski M, et al. MALDI imaging and profiling MS of higher mass proteins from tissue. J Am Soc Mass Spectrom. 2010;21:1922–29.

  49. 49.

    Todd PJ, Schaaff TG, Chaurand P, Caprioli RM. Organic ion imaging of biological tissue with secondary ion mass spectrometry and matrix-assisted laser desorption/ionization. J Mass Spectrom. 2001;36:355–69.

  50. 50.

    Zavalin A, Yang J, Hayden K, Vestal M, Caprioli RM. Tissue protein imaging at 1 mum laser spot diameter for high spatial resolution and high imaging speed using transmission geometry MALDI TOF MS. Anal Bioanal Chem. 2015;407:2337–42.

  51. 51.

    Ogrinc Potocnik N, Porta T, Becker M, Heeren RM, Ellis SR. Use of advantageous, volatile matrices enabled by next-generation high-speed matrix-assisted laser desorption/ionization time-of-flight imaging employing a scanning laser beam. Rapid Commun Mass Spectrom. 2015;29:2195–03.

  52. 52.

    Pol J, Strohalm M, Havlicek V, Volny M. Molecular mass spectrometry imaging in biomedical and life science research. Histochem Cell Biol. 2010;134:423–43.

  53. 53.

    Agar NY, Yang HW, Carroll RS, Black PM, Agar JN. Matrix solution fixation: histology-compatible tissue preparation for MALDI mass spectrometry imaging. Anal Chem. 2007;79:7416–23.

  54. 54.

    Takats Z, Wiseman JM, Gologan B, Cooks RG. Mass spectrometry sampling under ambient conditions with desorption electrospray ionization. Science. 2004;306:471–73.

  55. 55.

    Ifa DR, Wu C, Ouyang Z, Cooks RG. Desorption electrospray ionization and other ambient ionization methods: current progress and preview. Analyst. 2010;135:669–81.

  56. 56.

    Kertesz V, Van Berkel GJ. Improved imaging resolution in desorption electrospray ionization mass spectrometry. Rapid Commun Mass Spectrom. 2008;22:2639–44.

  57. 57.

    Muller L, Kailas A, Jackson SN, Roux A, Barbacci DC, Schultz JA, et al. Lipid imaging within the normal rat kidney using silver nanoparticles by matrix-assisted laser desorption/ionization mass spectrometry. Kidney Int. 2015;88:186–92.

  58. 58.

    Jackson SN, Barbacci D, Egan T, Lewis EK, Schultz JA, Woods AS. MALDI-ion mobility mass spectrometry of lipids in negative ion mode. Anal Methods. 2014;6:5001–07.

  59. 59.

    Jackson SN, Ugarov M, Egan T, Post JD, Langlais D, Albert Schultz J, et al. MALDI-ion mobility-TOFMS imaging of lipids in rat brain tissue. J Mass Spectrom. 2007;42:1093–98.

  60. 60.

    Caprioli RM. Imaging mass spectrometry: molecular microscopy for enabling a new age of discovery. Proteomics. 2014;14:807–9.

  61. 61.

    Norris JL, Caprioli RM. Imaging mass spectrometry: a new tool for pathology in a molecular age. Proteomics Clin Appl. 2013;7:733–38.

  62. 62.

    Stoeckli M, Chaurand P, Hallahan DE, Caprioli RM. Imaging mass spectrometry: a new technology for the analysis of protein expression in mammalian tissues. Nat Med. 2001;7:493–96.

  63. 63.

    Caprioli RM, Farmer TB, Gile J. Molecular imaging of biological samples: localization of peptides and proteins using MALDI-TOF MS. Anal Chem. 1997;69:4751–60.

  64. 64.

    Cazares LH, Troyer D, Mendrinos S, Lance RA, Nyalwidhe JO, Beydoun HA, et al. Imaging mass spectrometry of a specific fragment of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 2 discriminates cancer from uninvolved prostate tissue. Clin Cancer Res. 2009;15:5541–51.

  65. 65.

    Eberlin LS, Dill AL, Costa AB, Ifa DR, Cheng L, Masterson T, et al. Cholesterol sulfate imaging in human prostate cancer tissue by desorption electrospray ionization mass spectrometry. Anal Chem. 2010;82:3430–34.

  66. 66.

    Goto T, Terada N, Inoue T, Nakayama K, Okada Y, Yoshikawa T, et al. The expression profile of phosphatidylinositol in high spatial resolution imaging mass spectrometry as a potential biomarker for prostate cancer. PLoS ONE. 2014;9:e90242.

  67. 67.

    Jing Y, Zhang Z, Ma P, An S, Shen Y, Zhu L, et al. Concomitant BET and MAPK blockade for effective treatment of ovarian cancer. Oncotarget. 2016;7:2545–54.

  68. 68.

    Pallua JD, Schaefer G, Seifarth C, Becker M, Meding S, Rauser S, et al. MALDI-MS tissue imaging identification of biliverdin reductase B overexpression in prostate cancer. J Proteomics. 2013;91:500–14.

  69. 69.

    Powers TW, Neely BA, Shao Y, Tang H, Troyer DA, Mehta AS, et al. MALDI imaging mass spectrometry profiling of N-glycans in formalin-fixed paraffin embedded clinical tissue blocks and tissue microarrays. PLoS ONE. 2014;9:e106255.

  70. 70.

    Schwamborn K, Krieg RC, Reska M, Jakse G, Knuechel R, Wellmann A. Identifying prostate carcinoma by MALDI-Imaging. Int J Mol Med. 2007;20:155–59.

  71. 71.

    Wang X, Han J, Hardie DB, Yang J, Pan J, Borchers CH. Metabolomic profiling of prostate cancer by matrix assisted laser desorption/ionization-Fourier transform ion cyclotron resonance mass spectrometry imaging using matrix coating assisted by an electric field (MCAEF). Biochim Biophys Acta. 2017;1865:755–67.

  72. 72.

    Noguchi S, Yasui Y, Iwasaki J, Kumazaki M, Yamada N, Naito S, et al. Replacement treatment with microRNA-143 and -145 induces synergistic inhibition of the growth of human bladder cancer cells by regulating PI3K/Akt and MAPK signaling pathways. Cancer Lett. 2013;328:353–61.

  73. 73.

    Hanai J, Doro N, Sasaki AT, Kobayashi S, Cantley LC, Seth P, et al. Inhibition of lung cancer growth: ATP citrate lyase knockdown and statin treatment leads to dual blockade of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT pathways. J Cell Physiol. 2012;227:1709–20.

  74. 74.

    Yang SY, Miah A, Sales KM, Fuller B, Seifalian AM, Winslet M. Inhibition of the p38 MAPK pathway sensitises human colon cancer cells to 5-fluorouracil treatment. Int J Oncol. 2011;38:1695–02.

  75. 75.

    Yong HY, Koh MS, Moon A. The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer. Expert Opin Investig Drugs. 2009;18:1893–05.

  76. 76.

    Gibbs PE, Miralem T, Maines MD. Characterization of the human biliverdin reductase gene structure and regulatory elements: promoter activity is enhanced by hypoxia and suppressed by TNF-alpha-activated NF-kappaB. FASEB J. 2010;24:3239–54.

  77. 77.

    Gibbs PE, Miralem T, Maines MD. Biliverdin reductase: a target for cancer therapy? Front Pharmacol. 2015;6:119.

  78. 78.

    Kiguchi K, Iwamori M, Yamanouchi S, Ishiwata I, Saga M, Amemiya A. Coexpression of cholesterol sulfate and cytokeratin as tumor markers in well-differentiated squamous cell carcinoma of the human uterine cervix. Clin Cancer Res. 1998;4:2985–90.

  79. 79.

    Rearick JI, Stoner GD, George MA, Jetten AM. Cholesterol sulfate accumulation in tumorigenic and nontumorigenic rat esophageal epithelial cells: evidence for defective differentiation control in tumorigenic cells. Cancer Res. 1988;48:5289–95.

  80. 80.

    Wang X, Han J, Hardie DB, Yang J, Borchers CH. The use of matrix coating assisted by an electric field (MCAEF) to enhance mass spectrometric imaging of human prostate cancer biomarkers. J Mass Spectrom. 2016;51:86–95.

  81. 81.

    Guo S, Wang Y, Zhou D, Li Z. Electric field-assisted matrix coating method enhances the detection of small molecule metabolites for mass spectrometry imaging. Anal Chem. 2015;87:5860–65.

  82. 82.

    Chandler JD, Williams ED, Slavin JL, Best JD, Rogers S. Expression and localization of GLUT1 and GLUT12 in prostate carcinoma. r. 2003;97:2035–42.

  83. 83.

    Goto T, Terada N, Inoue T, Kobayashi T, Nakayama K, Okada Y, et al. Decreased expression of lysophosphatidylcholine (16:0/OH) in high resolution imaging mass spectrometry independently predicts biochemical recurrence after surgical treatment for prostate cancer. Prostate. 2015;75:1821–30.

  84. 84.

    Steurer S, Borkowski C, Odinga S, Buchholz M, Koop C, Huland H, et al. MALDI mass spectrometric imaging based identification of clinically relevant signals in prostate cancer using large-scale tissue microarrays. Int J Cancer 2013;133:920–28.

  85. 85.

    Nemes P, Vertes A. Atmospheric-pressure molecular imaging of biological tissues and biofilms by LAESI mass spectrometry. J Vis Exp. 2010;43:pii: 2097.

  86. 86.

    Calligaris D, Caragacianu D, Liu X, Norton I, Thompson CJ, Richardson AL, et al. Application of desorption electrospray ionization mass spectrometry imaging in breast cancer margin analysis. Proc Natl Acad Sci USA. 2014;111:15184–89.

  87. 87.

    Dekker TJ, Balluff BD, Jones EA, Schone CD, Schmitt M, Aubele M, et al. Multicenter matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) identifies proteomic differences in breast-cancer-associated stroma. J Proteome Res. 2014;13:4730–38.

  88. 88.

    Eberlin LS, Norton I, Dill AL, Golby AJ, Ligon KL, Santagata S, et al. Classifying human brain tumors by lipid imaging with mass spectrometry. Cancer Res. 2012;72:645–54.

  89. 89.

    Eberlin LS, Dill AL, Golby AJ, Ligon KL, Wiseman JM, Cooks RG, et al. Discrimination of human astrocytoma subtypes by lipid analysis using desorption electrospray ionization imaging mass spectrometry. Angew Chem Int Ed Engl. 2010;49:5953–56.

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Acknowledgements

This work was supported by PHS NIH grants R01CA115746 and R01CA115746-08S1 to L.L.C., and R01 CA201469 and P41EB015898 to N.Y.R.A., and by MGH Martinos Center for Biomedical Imaging.

Author contributions

A.K., L.A.V., and T.L.F.: literature research and manuscript preparation; P.H. and N.Y.R.A.: review; L.L.C.: funding, manuscript preparation, and review.

Author information

Affiliations

  1. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    • Annika Kurreck
    • , Lindsey A. Vandergrift
    • , Taylor L. Fuss
    •  & Leo L. Cheng
  2. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    • Annika Kurreck
    • , Lindsey A. Vandergrift
    • , Taylor L. Fuss
    •  & Leo L. Cheng
  3. Department of Hematology and Oncology, Charité Medical University of Berlin, Berlin, Germany

    • Annika Kurreck
    •  & Piet Habbel
  4. Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    • Nathalie Y. R. Agar
  5. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    • Nathalie Y. R. Agar
  6. Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    • Nathalie Y. R. Agar

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Conflict of interest

N.Y.R.A. is co-founder of BayesianDx and scientific advisor to inviCRO. The other authors declare that they have no competing interests.

Corresponding author

Correspondence to Leo L. Cheng.