Clinical and Pre-clinical Methods for Quantifying Tumor Hypoxia

  • Ashlyn G. Rickard
  • Gregory M. Palmer
  • Mark W. DewhirstEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1136)


Hypoxia, a prevalent characteristic of most solid malignant tumors, contributes to diminished therapeutic responses and more aggressive phenotypes. The term hypoxia has two definitions. One definition would be a physiologic state where the oxygen partial pressure is below the normal physiologic range. For most normal tissues, the normal physiologic range is between 10 and 20 mmHg. Hypoxic regions develop when there is an imbalance between oxygen supply and demand. The impact of hypoxia on cancer therapeutics is significant: hypoxic tissue is 3× less radiosensitive than normoxic tissue, the impaired blood flow found in hypoxic tumor regions influences chemotherapy delivery, and the immune system is dependent on oxygen for functionality. Despite the clinical implications of hypoxia, there is not a universal, ideal method for quantifying hypoxia, particularly cycling hypoxia because of its complexity and heterogeneity across tumor types and individuals. Most standard imaging techniques can be modified and applied to measuring hypoxia and quantifying its effects; however, the benefits and challenges of each imaging modality makes imaging hypoxia case-dependent. In this chapter, a comprehensive overview of the preclinical and clinical methods for quantifying hypoxia is presented along with the advantages and disadvantages of each.


Hypoxia Quantification Cycling hypoxia MRI/EPR Optical imaging PET 


  1. 1.
    Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26(2):225–239PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Moon EJ, Brizel DM, Chi JT, Dewhirst MW (2007) The potential role of intrinsic hypoxia markers as prognostic variables in cancer. Antioxid Redox Signal 9(8):1237–1294PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Braun RD, Lanzen JL, Snyder SA, Dewhirst MW (2001) Comparison of tumor and normal tissue oxygen tension measurements using OxyLite or microelectrodes in rodents. Am J Physiol Heart Circ Physiol 280(6):H2533–H2544PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Samoszuk MK, Walter J, Mechetner E (2004) Improved immunohistochemical method for detecting hypoxia gradients in mouse tissues and tumors. J Histochem Cytochem 52(6):837–839PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Arteel GE, Thurman RG, Yates JM, Raleigh JA (1995) Evidence that hypoxia markers detect oxygen gradients in liver: pimonidazole and retrograde perfusion of rat liver. Br J Cancer 72(4):889–895PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Dewhirst MW, Cao Y, Moeller B (2008) Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer 8(6):425–437PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Chitneni SK, Palmer GM, Zalutsky MR, Dewhirst MW (2011) Molecular imaging of hypoxia. J Nucl Med 52(2):165–168PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Brown JM, Wilson WR (2004) Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 4(6):437–447PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Sitkovsky MV, Hatfield S, Abbott R, Belikoff B, Lukashev D, Ohta A (2014) Hostile, hypoxia-A2-adenosinergic tumor biology as the next barrier to overcome for tumor immunologists. Cancer Immunol Res 2(7):598–605PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Ruan K, Song G, Ouyang G (2009) Role of hypoxia in the hallmarks of human cancer. J Cell Biochem 107(6):1053–1062PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Hatfield SM, Kjaergaard J, Lukashev D, Schreiber TH, Belikoff B, Abbott R et al (2015) Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci Transl Med 7(277):277ra30PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Sethumadhavan S, Silva M, Philbrook P, Nguyen T, Hatfield SM, Ohta A et al (2017) Hypoxia and hypoxia-inducible factor (HIF) downregulate antigen-presenting MHC class I molecules limiting tumor cell recognition by T cells. PLoS One 12(11):e0187314PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Dewhirst MW, Birer SR (2016) Oxygen-enhanced MRI is a major advance in tumor hypoxia imaging. Cancer Res 76(4):769–772PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Marcu L, Olver I (2006) Tirapazamine: from bench to clinical trials. Curr Clin Pharmacol 1(1):71–79PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Dewhirst MW, Ong ET, Braun RD, Smith B, Klitzman B, Evans SM et al (1999) Quantification of longitudinal tissue pO2 gradients in window chamber tumours: impact on tumour hypoxia. Br J Cancer 79(11–12):1717–1722PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Dewhirst MW, Ong ET, Klitzman B, Secomb TW, Vinuya RZ, Dodge R et al (1992) Perivascular oxygen tensions in a transplantable mammary tumor growing in a dorsal flap window chamber. Radiat Res 130(2):171–182PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Sorg BS, Hardee ME, Agarwal N, Moeller BJ, Dewhirst MW (2008) Spectral imaging facilitates visualization and measurements of unstable and abnormal microvascular oxygen transport in tumors. J Biomed Opt 13(1):014026PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Tomlinson RH, Gray LH (1955) The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 9(4):539–549CrossRefGoogle Scholar
  19. 19.
    Secomb TW, Hsu R, Dewhirst MW, Klitzman B, Gross JF (1993) Analysis of oxygen transport to tumor tissue by microvascular networks. Int J Radiat Oncol Biol Phys 25(3):481–489PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Secomb TW, Hsu R, Park EY, Dewhirst MW (2004) Green’s function methods for analysis of oxygen delivery to tissue by microvascular networks. Ann Biomed Eng 32(11):1519–1529PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Dewhirst MW, Kimura H, Rehmus SW, Braun RD, Papahadjopoulos D, Hong K et al (1996) Microvascular studies on the origins of perfusion-limited hypoxia. Br J Cancer Suppl 27:S247–S251PubMedPubMedCentralGoogle Scholar
  22. 22.
    Kavanagh BD, Coffey BE, Needham D, Hochmuth RM, Dewhirst MW (1993) The effect of flunarizine on erythrocyte suspension viscosity under conditions of extreme hypoxia, low pH, and lactate treatment. Br J Cancer 67(4):734–741PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Eddy HA, Casarett GW (1973) Development of the vascular system in the hamster malignant neurilemmoma. Microvasc Res 6(1):63–82PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Secomb TW, Hsu R, Ong ET, Gross JF, Dewhirst MW (1995) Analysis of the effects of oxygen supply and demand on hypoxic fraction in tumors. Acta Oncol 34(3):313–316PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Grimes DR, Warren DR, Warren S (2017) Hypoxia imaging and radiotherapy: bridging the resolution gap. Br J Radiol 90(1076):20160939PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Bristow RG, Hill RP (2008) Hypoxia and metabolism. hypoxia, DNA repair and genetic instability. Nat Rev Cancer 8(3):180–192PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Dewhirst MW (2009) Relationships between cycling hypoxia, HIF-1, angiogenesis and oxidative stress. Radiat Res 172(6):653–665PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Lanzen J, Braun RD, Klitzman B, Brizel D, Secomb TW, Dewhirst MW (2006) Direct demonstration of instabilities in oxygen concentrations within the extravascular compartment of an experimental tumor. Cancer Res 66(4):2219–2223PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Cardenas-Navia LI, Yu D, Braun RD, Brizel DM, Secomb TW, Dewhirst MW (2004) Tumor-dependent kinetics of partial pressure of oxygen fluctuations during air and oxygen breathing. Cancer Res 64(17):6010–6017PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Kimura H, Braun RD, Ong ET, Hsu R, Secomb TW, Papahadjopoulos D et al (1996) Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res 56(23):5522–5528PubMedGoogle Scholar
  31. 31.
    Braun RD, Lanzen JL, Dewhirst MW (1999) Fourier analysis of fluctuations of oxygen tension and blood flow in R3230Ac tumors and muscle in rats. Am J Phys 277(2 Pt 2):H551–H568Google Scholar
  32. 32.
    Skala MC, Fontanella A, Lan L, Izatt JA, Dewhirst MW (2010) Longitudinal optical imaging of tumor metabolism and hemodynamics. J Biomed Opt 15(1):011112PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Panek R, Welsh L, Baker LCJ, Schmidt MA, Wong KH, Riddell AM et al (2017) Noninvasive imaging of cycling hypoxia in head and neck cancer using intrinsic susceptibility MRI. Clin Cancer Res 23(15):4233–4241PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Moeller BJ, Cao Y, Li CY, Dewhirst MW (2004) Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5(5):429–441PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Chaplin DJ, Durand RE, Olive PL (1986) Acute hypoxia in tumors: implications for modifiers of radiation effects. Int J Radiat Oncol Biol Phys 12(8):1279–1282PubMedCrossRefGoogle Scholar
  36. 36.
    Thorwarth D, Eschmann SM, Paulsen F, Alber M (2007) Hypoxia dose painting by numbers: a planning study. Int J Radiat Oncol Biol Phys 68(1):291–300PubMedCrossRefGoogle Scholar
  37. 37.
    Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M et al (1998) Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394(6692):485–490PubMedCrossRefGoogle Scholar
  38. 38.
    Nam SY, Ko YS, Jung J, Yoon J, Kim YH, Choi YJ et al (2011) A hypoxia-dependent upregulation of hypoxia-inducible factor-1 by nuclear factor-kappaB promotes gastric tumour growth and angiogenesis. Br J Cancer 104(1):166–174PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Cosse JP, Michiels C (2008) Tumour hypoxia affects the responsiveness of cancer cells to chemotherapy and promotes cancer progression. Anti Cancer Agents Med Chem 8(7):790–797CrossRefGoogle Scholar
  40. 40.
    Ueda S, Roblyer D, Cerussi A, Durkin A, Leproux A, Santoro Y et al (2012) Baseline tumor oxygen saturation correlates with a pathologic complete response in breast cancer patients undergoing neoadjuvant chemotherapy. Cancer Res 72(17):4318–4328PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Dasu A, Toma-Dasu I (2008) Vascular oxygen content and the tissue oxygenation – a theoretical analysis. Med Phys 35(2):539–545PubMedCrossRefGoogle Scholar
  42. 42.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247CrossRefGoogle Scholar
  43. 43.
    Fournier L, Ammari S, Thiam R, Cuenod CA (2014) Imaging criteria for assessing tumour response: RECIST, mRECIST, Cheson. Diagn Interv Imaging 95(7–8):689–703PubMedCrossRefGoogle Scholar
  44. 44.
    Martens MH, Lambregts DMJ, Kluza E, Beets-Tan RGH (2014) Tumor response to treatment: prediction and assessment. Curr Radiol Rep 2(9):62CrossRefGoogle Scholar
  45. 45.
    Humbert O, Berriolo-Riedinger A, Cochet A, Gauthier M, Charon-Barra C, Guiu S et al (2014) Prognostic relevance at 5 years of the early monitoring of neoadjuvant chemotherapy using (18)F-FDG PET in luminal HER2-negative breast cancer. Eur J Nucl Med Mol Imaging 41(3):416–427PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Di Renzo GC, Luzi G, Cucchia GC, Caserta G, Fusaro P, Perdikaris A et al (1992) The role of Doppler technology in the evaluation of fetal hypoxia. Early Hum Dev 29(1–3):259–267PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Peeters SG, Zegers CM, Lieuwes NG, van Elmpt W, Eriksson J, van Dongen GA et al (2015) A comparative study of the hypoxia PET tracers [(1)(8)F]HX4, [(1)(8)F]FAZA, and [(1)(8)F]FMISO in a preclinical tumor model. Int J Radiat Oncol Biol Phys 91(2):351–359PubMedCrossRefGoogle Scholar
  48. 48.
    Mirabello V, Cortezon-Tamarit F, Pascu SI (2018) Oxygen sensing, hypoxia tracing and in vivo imaging with functional metalloprobes for the early detection of non-communicable diseases. Front Chem 6:27PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Chapman JD, Franko AJ, Sharplin J (1981) A marker for hypoxic cells in tumours with potential clinical applicability. Br J Cancer 43(4):546–550PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Rasey JS, Grunbaum Z, Magee S, Nelson NJ, Olive PL, Durand RE et al (1987) Characterization of radiolabeled fluoromisonidazole as a probe for hypoxic cells. Radiat Res 111(2):292–304PubMedCrossRefGoogle Scholar
  51. 51.
    Jerabek PA, Patrick TB, Kilbourn MR, Dischino DD, Welch MJ (1986) Synthesis and biodistribution of 18F-labeled fluoronitroimidazoles: potential in vivo markers of hypoxic tissue. Int J Rad Appl Instrum A 37(7):599–605PubMedCrossRefGoogle Scholar
  52. 52.
    Ljungkvist AS, Bussink J, Kaanders JH, van der Kogel AJ (2007) Dynamics of tumor hypoxia measured with bioreductive hypoxic cell markers. Radiat Res 167(2):127–145PubMedCrossRefGoogle Scholar
  53. 53.
    Rajendran JG, Krohn KA (2005) Imaging hypoxia and angiogenesis in tumors. Radiol Clin N Am 43(1):169–187PubMedCrossRefGoogle Scholar
  54. 54.
    Gagel B, Reinartz P, Dimartino E, Zimny M, Pinkawa M, Maneschi P et al (2004) pO(2) Polarography versus positron emission tomography ([(18)F] fluoromisonidazole, [(18)F]-2-fluoro-2′-deoxyglucose). An appraisal of radiotherapeutically relevant hypoxia. Strahlenther Onkol 180(10):616–622PubMedCrossRefGoogle Scholar
  55. 55.
    Padhani AR, Krohn KA, Lewis JS, Alber M (2007) Imaging oxygenation of human tumours. Eur Radiol 17(4):861–872PubMedCrossRefGoogle Scholar
  56. 56.
    Lee NY, Mechalakos JG, Nehmeh S, Lin Z, Squire OD, Cai S et al (2008) Fluorine-18-labeled fluoromisonidazole positron emission and computed tomography-guided intensity-modulated radiotherapy for head and neck cancer: a feasibility study. Int J Radiat Oncol Biol Phys 70(1):2–13PubMedCrossRefGoogle Scholar
  57. 57.
    Hendrickson K, Phillips M, Smith W, Peterson L, Krohn K, Rajendran J (2011) Hypoxia imaging with [F-18] FMISO-PET in head and neck cancer: potential for guiding intensity modulated radiation therapy in overcoming hypoxia-induced treatment resistance. Radiother Oncol 101(3):369–375PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Eschmann SM, Paulsen F, Reimold M, Dittmann H, Welz S, Reischl G et al (2005) Prognostic impact of hypoxia imaging with 18F-misonidazole PET in non-small cell lung cancer and head and neck cancer before radiotherapy. J Nucl Med 46(2):253–260PubMedGoogle Scholar
  59. 59.
    Rajendran JG, Mankoff DA, O’Sullivan F, Peterson LM, Schwartz DL, Conrad EU et al (2004) Hypoxia and glucose metabolism in malignant tumors: evaluation by [18F]fluoromisonidazole and [18F]fluorodeoxyglucose positron emission tomography imaging. Clin Cancer Res 10(7):2245–2252PubMedCrossRefGoogle Scholar
  60. 60.
    Lawrentschuk N, Poon AM, Foo SS, Putra LG, Murone C, Davis ID et al (2005) Assessing regional hypoxia in human renal tumours using 18F-fluoromisonidazole positron emission tomography. BJU Int 96(4):540–546CrossRefPubMedGoogle Scholar
  61. 61.
    Bruehlmeier M, Roelcke U, Schubiger PA, Ametamey SM (2004) Assessment of hypoxia and perfusion in human brain tumors using PET with 18F-fluoromisonidazole and 15O-H2O. J Nucl Med 45(11):1851–1859PubMedPubMedCentralGoogle Scholar
  62. 62.
    Spence AM, Muzi M, Swanson KR, O’Sullivan F, Rockhill JK, Rajendran JG et al (2008) Regional hypoxia in glioblastoma multiforme quantified with [18F]fluoromisonidazole positron emission tomography before radiotherapy: correlation with time to progression and survival. Clin Cancer Res 14(9):2623–2630PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Hugonnet F, Fournier L, Medioni J, Smadja C, Hindie E, Huchet V et al (2011) Metastatic renal cell carcinoma: relationship between initial metastasis hypoxia, change after 1 month’s sunitinib, and therapeutic response: an 18F-fluoromisonidazole PET/CT study. J Nucl Med 52(7):1048–1055PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Grkovski M, Lee NY, Schoder H, Carlin SD, Beattie BJ, Riaz N et al (2017) Monitoring early response to chemoradiotherapy with (18)F-FMISO dynamic PET in head and neck cancer. Eur J Nucl Med Mol Imaging 44(10):1682–1691PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Rischin D, Hicks RJ, Fisher R, Binns D, Corry J, Porceddu S et al (2006) Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of Trans-Tasman Radiation Oncology Group Study 98.02. J Clin Oncol 24(13):2098–2104PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Dolbier WR Jr, Li AR, Koch CJ, Shiue CY, Kachur AV (2001) [18F]-EF5, a marker for PET detection of hypoxia: synthesis of precursor and a new fluorination procedure. Appl Radiat Isot 54(1):73–80PubMedCrossRefGoogle Scholar
  67. 67.
    Chitneni SK, Bida GT, Yuan H, Palmer GM, Hay MP, Melcher T et al (2013) 18F-EF5 PET imaging as an early response biomarker for the hypoxia-activated prodrug SN30000 combined with radiation treatment in a non-small cell lung cancer xenograft model. J Nucl Med 54(8):1339–1346PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Ali R, Apte S, Vilalta M, Subbarayan M, Miao Z, Chin FT et al (2015) 18F-EF5 PET is predictive of response to fractionated radiotherapy in preclinical tumor models. PLoS One 10(10):e0139425PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Chitneni SK, Bida GT, Zalutsky MR, Dewhirst MW (2014) Comparison of the hypoxia PET tracer (18)F-EF5 to immunohistochemical marker EF5 in 3 different human tumor xenograft models. J Nucl Med 55(7):1192–1197PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Qian Y, Von Eyben R, Liu Y, Chin FT, Miao Z, Apte S et al (2018) (18)F-EF5 PET-based imageable hypoxia predicts local recurrence in tumors treated with highly conformal radiation therapy. Int J Radiat Oncol Biol Phys 102:1183–1192PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Manzoor AA, Yuan H, Palmer GM, Vigilanti BL, Dewhirst MW (2010) Imaging hypoxia. In: Molecular imaging: principles and practice. People’s Medical Publishing House, Shelton, pp 756–780Google Scholar
  72. 72.
    Lapi SE, Lewis JS, Dehdashti F (2015) Evaluation of hypoxia with copper-labeled diacetyl-bis(N-methylthiosemicarbazone). Semin Nucl Med 45(2):177–185PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Dehdashti F, Mintun MA, Lewis JS, Bradley J, Govindan R, Laforest R et al (2003) In vivo assessment of tumor hypoxia in lung cancer with 60Cu-ATSM. Eur J Nucl Med Mol Imaging 30(6):844–850PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Dehdashti F, Grigsby PW, Mintun MA, Lewis JS, Siegel BA, Welch MJ (2003) Assessing tumor hypoxia in cervical cancer by positron emission tomography with 60Cu-ATSM: relationship to therapeutic response-a preliminary report. Int J Radiat Oncol Biol Phys 55(5):1233–1238PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Zhang T, Das SK, Fels DR, Hansen KS, Wong TZ, Dewhirst MW et al (2013) PET with 62Cu-ATSM and 62Cu-PTSM is a useful imaging tool for hypoxia and perfusion in pulmonary lesions. AJR Am J Roentgenol 201(5):W698–W706PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Thulborn KR, Waterton JC, Matthews PM, Radda GK (1982) Oxygenation dependence of the transverse relaxation time of water protons in whole blood at high field. Biochim Biophys Acta 714(2):265–270PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Howe FA, Robinson SP, McIntyre DJ, Stubbs M, Griffiths JR (2001) Issues in flow and oxygenation dependent contrast (FLOOD) imaging of tumours. NMR Biomed 14(7–8):497–506PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Ogawa S, Lee TM, Kay AR, Tank DW (1990) Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci U S A 87(24):9868–9872PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Baudelet C, Gallez B (2002) How does blood oxygen level-dependent (BOLD) contrast correlate with oxygen partial pressure (pO2) inside tumors? Magn Reson Med 48(6):980–986PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Chopra S, Foltz WD, Milosevic MF, Toi A, Bristow RG, Menard C et al (2009) Comparing oxygen-sensitive MRI (BOLD R2*) with oxygen electrode measurements: a pilot study in men with prostate cancer. Int J Radiat Biol 85(9):805–813PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Hoskin PJ, Carnell DM, Taylor NJ, Smith RE, Stirling JJ, Daley FM et al (2007) Hypoxia in prostate cancer: correlation of BOLD-MRI with pimonidazole immunohistochemistry-initial observations. Int J Radiat Oncol Biol Phys 68(4):1065–1071PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Taylor NJ, Baddeley H, Goodchild KA, Powell ME, Thoumine M, Culver LA et al (2001) BOLD MRI of human tumor oxygenation during carbogen breathing. J Magn Reson Imaging 14(2):156–163PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Jiang L, Weatherall PT, McColl RW, Tripathy D, Mason RP (2013) Blood oxygenation level-dependent (BOLD) contrast magnetic resonance imaging (MRI) for prediction of breast cancer chemotherapy response: a pilot study. J Magn Reson Imaging 37(5):1083–1092PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Neeman M, Dafni H, Bukhari O, Braun RD, Dewhirst MW (2001) In vivo BOLD contrast MRI mapping of subcutaneous vascular function and maturation: validation by intravital microscopy. Magn Reson Med 45(5):887–898PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Dunn TJ, Braun RD, Rhemus WE, Rosner GL, Secomb TW, Tozer GM et al (1999) The effects of hyperoxic and hypercarbic gases on tumour blood flow. Br J Cancer 80(1–2):117–126PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Mark CI, Mazerolle EL, Chen JJ (2015) Metabolic and vascular origins of the BOLD effect: implications for imaging pathology and resting-state brain function. J Magn Reson Imaging 42(2):231–246PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Ruiz-Cabello J, Barnett BP, Bottomley PA, Bulte JW (2011) Fluorine (19F) MRS and MRI in biomedicine. NMR Biomed 24(2):114–129PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Yu JX, Kodibagkar VD, Cui W, Mason RP (2005) 19F: a versatile reporter for non-invasive physiology and pharmacology using magnetic resonance. Curr Med Chem 12(7):819–848PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Hunjan S, Zhao D, Constantinescu A, Hahn EW, Antich PP, Mason RP (2001) Tumor oximetry: demonstration of an enhanced dynamic mapping procedure using fluorine-19 echo planar magnetic resonance imaging in the Dunning prostate R3327-AT1 rat tumor. Int J Radiat Oncol Biol Phys 49(4):1097–1108PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Mason RP, Antich PP, Babcock EE, Constantinescu A, Peschke P, Hahn EW (1994) Non-invasive determination of tumor oxygen tension and local variation with growth. Int J Radiat Oncol Biol Phys 29(1):95–103PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Noth U, Rodrigues LM, Robinson SP, Jork A, Zimmermann U, Newell B et al (2004) In vivo determination of tumor oxygenation during growth and in response to carbogen breathing using 15C5-loaded alginate capsules as fluorine-19 magnetic resonance imaging oxygen sensors. Int J Radiat Oncol Biol Phys 60(3):909–919PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Young IR, Clarke GJ, Bailes DR, Pennock JM, Doyle FH, Bydder GM (1981) Enhancement of relaxation rate with paramagnetic contrast agents in NMR imaging. J Comput Tomogr 5(6):543–547PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Berkowitz BA (1997) Role of dissolved plasma oxygen in hyperoxia-induced contrast. Magn Reson Imaging 15(1):123–126PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    O’Connor JP, Boult JK, Jamin Y, Babur M, Finegan KG, Williams KJ et al (2016) Oxygen-enhanced MRI accurately identifies, quantifies, and maps tumor hypoxia in preclinical cancer models. Cancer Res 76(4):787–795PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Matsumoto K, Bernardo M, Subramanian S, Choyke P, Mitchell JB, Krishna MC et al (2006) MR assessment of changes of tumor in response to hyperbaric oxygen treatment. Magn Reson Med 56(2):240–246PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Hallac RR, Zhou H, Pidikiti R, Song K, Stojadinovic S, Zhao D et al (2014) Correlations of noninvasive BOLD and TOLD MRI with pO2 and relevance to tumor radiation response. Magn Reson Med 71(5):1863–1873PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Linnik IV, Scott ML, Holliday KF, Woodhouse N, Waterton JC, O’Connor JP et al (2014) Noninvasive tumor hypoxia measurement using magnetic resonance imaging in murine U87 glioma xenografts and in patients with glioblastoma. Magn Reson Med 71(5):1854–1862PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Zhao D, Pacheco-Torres J, Hallac RR, White D, Peschke P, Cerdan S et al (2015) Dynamic oxygen challenge evaluated by NMR T1 and T2*--insights into tumor oxygenation. NMR Biomed 28(8):937–947PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Falk SJ, Ward R, Bleehen NM (1992) The influence of carbogen breathing on tumour tissue oxygenation in man evaluated by computerised p02 histography. Br J Cancer 66(5):919–924PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Le D, Mason RP, Hunjan S, Constantinescu A, Barker BR, Antich PP (1997) Regional tumor oxygen dynamics: 19F PBSR EPI of hexafluorobenzene. Magn Reson Imaging 15(8):971–981PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Duling BR, Berne RM (1970) Longitudinal gradients in periarteriolar oxygen tension. A possible mechanism for the participation of oxygen in local regulation of blood flow. Circ Res 27(5):669–678PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Dewhirst MW, Ong ET, Rosner GL, Rehmus SW, Shan S, Braun RD et al (1996) Arteriolar oxygenation in tumour and subcutaneous arterioles: effects of inspired air oxygen content. Br J Cancer Suppl 27:S241–S246PubMedPubMedCentralGoogle Scholar
  103. 103.
    Erickson K, Braun RD, Yu D, Lanzen J, Wilson D, Brizel DM et al (2003) Effect of longitudinal oxygen gradients on effectiveness of manipulation of tumor oxygenation. Cancer Res 63(15):4705–4712PubMedPubMedCentralGoogle Scholar
  104. 104.
    Colliez F, Gallez B, Jordan BF (2017) Assessing tumor oxygenation for predicting outcome in radiation oncology: a review of studies correlating tumor hypoxic status and outcome in the preclinical and clinical settings. Front Oncol 7:10PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Krishna MC, Matsumoto S, Yasui H, Saito K, Devasahayam N, Subramanian S et al (2012) Electron paramagnetic resonance imaging of tumor pO(2). Radiat Res 177(4):376–386PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Gallez B, Baudelet C, Jordan BF (2004) Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications. NMR Biomed 17(5):240–262PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Subramanian S, Matsumoto K, Mitchell JB, Krishna MC (2004) Radio frequency continuous-wave and time-domain EPR imaging and overhauser-enhanced magnetic resonance imaging of small animals: instrumental developments and comparison of relative merits for functional imaging. NMR Biomed 17(5):263–294PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Tatum JL, Kelloff GJ, Gillies RJ, Arbeit JM, Brown JM, Chao KS et al (2006) Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int J Radiat Biol 82(10):699–757PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Ilangovan G, Li H, Zweier JL, Kuppusamy P (2002) In vivo measurement of tumor redox environment using EPR spectroscopy. Mol Cell Biochem 234–235(1–2):393–398PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Hou H, Abramovic Z, Lariviere JP, Sentjurc M, Swartz H, Khan N (2010) Effect of a topical vasodilator on tumor hypoxia and tumor oxygen guided radiotherapy using EPR oximetry. Radiat Res 173(5):651–658PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Hou H, Dong R, Lariviere JP, Mupparaju SP, Swartz HM, Khan N (2011) Synergistic combination of hyperoxygenation and radiotherapy by repeated assessments of tumor pO2 with EPR oximetry. J Radiat Res 52(5):568–574PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Hou H, Lariviere JP, Demidenko E, Gladstone D, Swartz H, Khan N (2009) Repeated tumor pO(2) measurements by multi-site EPR oximetry as a prognostic marker for enhanced therapeutic efficacy of fractionated radiotherapy. Radiother Oncol 91(1):126–131PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Goda F, Bacic G, O’Hara JA, Gallez B, Swartz HM, Dunn JF (1996) The relationship between partial pressure of oxygen and perfusion in two murine tumors after X-ray irradiation: a combined gadopentetate dimeglumine dynamic magnetic resonance imaging and in vivo electron paramagnetic resonance oximetry study. Cancer Res 56(14):3344–3349PubMedPubMedCentralGoogle Scholar
  114. 114.
    Goda F, O’Hara JA, Rhodes ES, Liu KJ, Dunn JF, Bacic G et al (1995) Changes of oxygen tension in experimental tumors after a single dose of X-ray irradiation. Cancer Res 55(11):2249–2252PubMedPubMedCentralGoogle Scholar
  115. 115.
    Ansiaux R, Baudelet C, Jordan BF, Beghein N, Sonveaux P, De Wever J et al (2005) Thalidomide radiosensitizes tumors through early changes in the tumor microenvironment. Clin Cancer Res 11(2 Pt 1):743–750PubMedPubMedCentralGoogle Scholar
  116. 116.
    Jordan BF, Gregoire V, Demeure RJ, Sonveaux P, Feron O, O’Hara J et al (2002) Insulin increases the sensitivity of tumors to irradiation: involvement of an increase in tumor oxygenation mediated by a nitric oxide-dependent decrease of the tumor cells oxygen consumption. Cancer Res 62(12):3555–3561PubMedPubMedCentralGoogle Scholar
  117. 117.
    Elas M, Bell R, Hleihel D, Barth ED, McFaul C, Haney CR et al (2008) Electron paramagnetic resonance oxygen image hypoxic fraction plus radiation dose strongly correlates with tumor cure in FSa fibrosarcomas. Int J Radiat Oncol Biol Phys 71(2):542–549PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Hou H, Mupparaju SP, Lariviere JP, Hodge S, Gui J, Swartz HM et al (2013) Assessment of the changes in 9L and C6 glioma pO2 by EPR oximetry as a prognostic indicator of differential response to radiotherapy. Radiat Res 179(3):343–351PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Ardenkjaer-Larsen JH, Laursen I, Leunbach I, Ehnholm G, Wistrand LG, Petersson JS et al (1998) EPR and DNP properties of certain novel single electron contrast agents intended for oximetric imaging. J Magn Reson 133(1):1–12PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Elas M, Ahn KH, Parasca A, Barth ED, Lee D, Haney C et al (2006) Electron paramagnetic resonance oxygen images correlate spatially and quantitatively with Oxylite oxygen measurements. Clin Cancer Res 12(14 Pt 1):4209–4217PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Matsumoto S, Yasui H, Mitchell JB, Krishna MC (2010) Imaging cycling tumor hypoxia. Cancer Res 70(24):10019–10023PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Matsumoto S, Hyodo F, Subramanian S, Devasahayam N, Munasinghe J, Hyodo E et al (2008) Low-field paramagnetic resonance imaging of tumor oxygenation and glycolytic activity in mice. J Clin Invest 118(5):1965–1973PubMedPubMedCentralGoogle Scholar
  123. 123.
    Matsumoto S, Batra S, Saito K, Yasui H, Choudhuri R, Gadisetti C et al (2011) Antiangiogenic agent sunitinib transiently increases tumor oxygenation and suppresses cycling hypoxia. Cancer Res 71(20):6350–6359PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Zijlstra WG, Buursma A (1991) Meeuwsen-van der Roest WP. Absorption spectra of human fetal and adult oxyhemoglobin, de-oxyhemoglobin, carboxyhemoglobin, and methemoglobin. Clin Chem 37(9):1633–1638PubMedPubMedCentralGoogle Scholar
  125. 125.
    Leow MK (2007) Configuration of the hemoglobin oxygen dissociation curve demystified: a basic mathematical proof for medical and biological sciences undergraduates. Adv Physiol Educ 31(2):198–201PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Severinghaus JW (1979) Simple, accurate equations for human blood O2 dissociation computations. J Appl Physiol Respir Environ Exerc Physiol 46(3):599–602PubMedPubMedCentralGoogle Scholar
  127. 127.
    van der Sanden BP, Heerschap A, Hoofd L, Simonetti AW, Nicolay K, van der Toorn A et al (1999) Effect of carbogen breathing on the physiological profile of human glioma xenografts. Magn Reson Med 42(3):490–499PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Baikejiang R, Zhang W, Li C (2017) Diffuse optical tomography for breast cancer imaging guided by computed tomography: a feasibility study. J Xray Sci Technol 25(3):341–355PubMedPubMedCentralGoogle Scholar
  129. 129.
    Kim MJ, Su MY, Yu HJ, Chen JH, Kim EK, Moon HJ et al (2016) US-localized diffuse optical tomography in breast cancer: comparison with pharmacokinetic parameters of DCE-MRI and with pathologic biomarkers. BMC Cancer 16:50PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Gunther JE, Lim EA, Kim HK, Flexman M, Altoe M, Campbell JA et al (2018) Dynamic diffuse optical tomography for monitoring neoadjuvant chemotherapy in patients with breast cancer. Radiology 287(3):778–786PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Tromberg BJ, Pogue BW, Paulsen KD, Yodh AG, Boas DA, Cerussi AE (2008) Assessing the future of diffuse optical imaging technologies for breast cancer management. Med Phys 35(6):2443–2451PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Erickson PR, Moor KJ, Werner JJ, Latch DE, Arnold WA, McNeill K (2018) Singlet oxygen phosphorescence as a probe for triplet-state dissolved organic matter reactivity. Environ Sci Technol 52(16):9170–9178PubMedCrossRefGoogle Scholar
  133. 133.
    DeRosa CA, Samonina-Kosicka J, Fan Z, Hendargo HC, Weitzel DH, Palmer GM et al (2015) Oxygen sensing difluoroboron dinaphthoylmethane polylactide. Macromolecules 48(9):2967–2977PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Palmer GM, Fontanella AN, Zhang G, Hanna G, Fraser CL, Dewhirst MW (2010) Optical imaging of tumor hypoxia dynamics. J Biomed Opt 15(6):066021PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Wilson DF, Evans SM, Jenkins WT, Vinogradov SA, Ong E, Dewhirst MW (1998) Oxygen distributions within R3230Ac tumors growing in dorsal flap window chambers in rats. Adv Exp Med Biol 454:603–609PubMedCrossRefGoogle Scholar
  136. 136.
    Cardenas-Navia LI, Mace D, Richardson RA, Wilson DF, Shan S, Dewhirst MW (2008) The pervasive presence of fluctuating oxygenation in tumors. Cancer Res 68(14):5812–5819PubMedCrossRefGoogle Scholar
  137. 137.
    Overgaard J, Horsman MR (1996) Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and sensitizers. Semin Radiat Oncol 6(1):10–21PubMedCrossRefGoogle Scholar
  138. 138.
    Fontanella AN, Schroeder T, Hochman DW, Chen RE, Hanna G, Haglund MM et al (2013) Quantitative mapping of hemodynamics in the lung, brain, and dorsal window chamber-grown tumors using a novel, automated algorithm. Microcirculation 20(8):724–735PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Ashlyn G. Rickard
    • 1
  • Gregory M. Palmer
    • 1
  • Mark W. Dewhirst
    • 1
    Email author
  1. 1.Department of Radiation OncologyDuke UniversityDurhamUSA

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