Dependency of the blood oxygen level dependent-response to hyperoxic challenges on the order of gas administration in intracranial malignancies
Literature reports contradicting results on the response of brain tumors to vascular stimuli measured in T2*-weighted MRI. Here, we analyzed the potential dependency of the MRI-response to (hypercapnic) hyperoxia on the order of the gas administration.
T2* values were quantified at 3 Tesla in eight consenting patients at rest and during inhalation of hyperoxic/hypercapnic gas mixtures. Patients were randomly divided into two groups undergoing different gas administration protocols (group A: medical air-pure oxygen–carbogen; group B: medical air–carbogen-pure oxygen). Mann-Whitney U test and Wilcoxon signed rank test have been used to proof differences in T2* regarding respiratory challenge or different groups, respectively.
T2* values at rest for gray and white matter were 50.3 ± 2.6 ms and 46.1 ± 2.0 ms, respectively, and slightly increased during challenge. In tumor areas, T2* at rest were: necrosis = 74.1 ± 10.1 ms; edema = 60.3 ± 17.6 ms; contrast-enhancing lesions = 48.6 ± 20.7 ms; and solid T2-hyperintense lesions = 45.0 ± 3.0 ms. Contrast-enhancing lesions strongly responded to oxygen (+ 20.7%) regardless on the gas protocol (p = 0.482). However, the response to carbogen significantly depended on the order of gas administration (group A, + 18.6%; group B, − 6.4%, p = 0.042). In edemas, a different trend between group was found when breathing oxygen (group A, − 9.9%; group B, + 19.5%, p = 0.057).
Preliminary results show a dependency of the T2* response of contrast-enhancing brain tumor lesions on the order of the gas administration. The gas administration protocol is an important factor in the interpretation of the T2*-response in areas of abnormal vascular growth.
KeywordsBOLD MRI Oxygen Carbogen T2* R2* Vascular reactivity
This work was supported by the CRPP Tumor Oxygenation of the University of Zurich and by the CRPP Molecular Imaging Network Zurich (minz) of the University of Zurich.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 4.Taylor NJ, Baddeley H, Goodchild KA, Powell ME, Thoumine M, Culver LA, Stirling JJ, Saunders MI, Hoskin PJ, Phillips H, Padhani AR, Griffiths JR (2001) BOLD MRI of human tumor oxygenation during carbogen breathing. J Magn Reson Imaging 14(2):156–163Google Scholar
- 7.Rossi C, Boss A, Donati OF, Luechinger R, Kollias SS, Valavanis A, Hodler J, Nanz D (2012) Manipulation of cortical gray matter oxygenation by hyperoxic respiratory challenge: field dependence of R(2) * and MR signal response. NMR Biomed 25(8):1007–1014. https://doi.org/10.1002/nbm.2775 Google Scholar
- 8.Morgan TJ (1999) The oxyhaemoglobin dissociation curve in critical illness. Crit Care Resusc 1(1):93–100Google Scholar
- 9.Thiel S, Lettau F, Rejmer P, Rossi C, Haile SR, Schwarz EI, Stoberl AS, Sievi NA, Boss A, Becker AS, Winklhofer S, Stradling JR, Kohler M (2018) Effects of short-term CPAP withdrawal on cerebral vascular reactivity measured by BOLD MRI in OSA: a randomised controlled trial. Eur Respir J 53:1801854. https://doi.org/10.1183/13993003.01854-2018 Google Scholar
- 10.Sobczyk O, Battisti-Charbonney A, Fierstra J, Mandell DM, Poublanc J, Crawley AP, Mikulis DJ, Duffin J, Fisher JA (2014) A conceptual model for CO(2)-induced redistribution of cerebral blood flow with experimental confirmation using BOLD MRI. Neuroimage 92:56–68. https://doi.org/10.1016/j.neuroimage.2014.01.051 Google Scholar
- 11.De Vis JB, Bhogal AA, Hendrikse J, Petersen ET, Siero JCW (2018) Effect sizes of BOLD CVR, resting-state signal fluctuations and time delay measures for the assessment of hemodynamic impairment in carotid occlusion patients. Neuroimage 179:530–539Google Scholar
- 12.Chakhoyan A, Corroyer-Dulmont A, Leblond MM, Gerault A, Toutain J, Chazaviel L, Divoux D, Petit E, MacKenzie ET, Kauffmann F, Delcroix N, Bernaudin M, Touzani O, Valable S (2017) Carbogen-induced increases in tumor oxygenation depend on the vascular status of the tumor: a multiparametric MRI study in two rat glioblastoma models. J Cereb Blood Flow Metab 37(6):2270–2282. https://doi.org/10.1177/0271678X16663947 Google Scholar
- 13.Cao-Pham TT, Joudiou N, Van Hul M, Bouzin C, Cani PD, Gallez B, Jordan BF (2017) Combined endogenous MR biomarkers to predict basal tumor oxygenation and response to hyperoxic challenge. NMR Biomed 30(12). https://doi.org/10.1002/nbm.3836
- 14.Cao-Pham TT, Tran LB, Colliez F, Joudiou N, El Bachiri S, Gregoire V, Leveque P, Gallez B, Jordan BF (2016) Monitoring tumor response to carbogen breathing by oxygen-sensitive magnetic resonance parameters to predict the outcome of radiation therapy: a preclinical study. Int J Radiat Oncol Biol Phys 96(1):149–160. https://doi.org/10.1016/j.ijrobp.2016.04.029 Google Scholar
- 15.Li D, Wang X, Wang S, Cheng J (2015) Correlation between BOLD-MRI and HIF expression level in renal carcinoma. Int J Clin Exp Pathol 8(10):13759–13763Google Scholar
- 21.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):497–506Google Scholar
- 23.Fan X, River JN, Zamora M, Al-Hallaq HA, Karczmar GS (2002) Effect of carbogen on tumor oxygenation: combined fluorine-19 and proton MRI measurements. Int J Radiat Oncol Biol Phys 54(4):1202–1209Google Scholar
- 24.Muller A, Remmele S, Wenningmann I, Clusmann H, Traber F, Flacke S, Konig R, Gieseke J, Willinek WA, Schild HH, Murtz P (2010) Intracranial tumor response to respiratory challenges at 3.0 T: impact of different methods to quantify changes in the MR relaxation rate R2*. J Magn Reson Imaging 32(1):17–23. https://doi.org/10.1002/jmri.22205 Google Scholar
- 25.Muller A, Remmele S, Wenningmann I, Clusmann H, Traber F, Flacke S, Konig R, Gieseke J, Willinek WA, Schild HH, Murtz P (2011) Analysing the response in R2* relaxation rate of intracranial tumours to hyperoxic and hypercapnic respiratory challenges: initial results. Eur Radiol 21(4):786–798. https://doi.org/10.1007/s00330-010-1948-7 Google Scholar
- 27.Remmele S, Dahnke H, Flacke S, Soehle M, Wenningmann I, Kovacs A, Traber F, Muller A, Willinek WA, Konig R, Clusmann H, Gieseke J, Schild HH, Murtz P (2010) Quantification of the magnetic resonance signal response to dynamic (C)O(2)-enhanced imaging in the brain at 3 T: R*(2) BOLD vs. balanced SSFP. J Magn Reson Imaging 31(6):1300–1310. https://doi.org/10.1002/jmri.22171 Google Scholar
- 30.Safronova MM, Colliez F, Magat J, Joudiou N, Jordan BF, Raftopoulos C, Gallez B, Duprez T (2016) Mapping of global R1 and R2* values versus lipids R1 values as potential markers of hypoxia in human glial tumors: a feasibility study. Magn Reson Imaging 34(2):105–113. https://doi.org/10.1016/j.mri.2015.10.021 Google Scholar
- 31.Preibisch C, Shi K, Kluge A, Lukas M, Wiestler B, Gottler J, Gempt J, Ringel F, Al Jaberi M, Schlegel J, Meyer B, Zimmer C, Pyka T, Forster S (2017) Characterizing hypoxia in human glioma: a simultaneous multimodal MRI and PET study. NMR Biomed 30(11). https://doi.org/10.1002/nbm.3775
- 32.Bane O, Besa C, Wagner M, Oesingmann N, Zhu H, Fiel MI, Taouli B (2016) Feasibility and reproducibility of BOLD and TOLD measurements in the liver with oxygen and carbogen gas challenge in healthy volunteers and patients with hepatocellular carcinoma. J Magn Reson Imaging 43(4):866–876. https://doi.org/10.1002/jmri.25051 Google Scholar
- 33.Ozbay PS, Stieb S, Rossi C, Riesterer O, Boss A, Weiss T, Kuhn FP, Pruessmann KP, Nanz D (2018) Lesion magnetic susceptibility response to hyperoxic challenge: a biomarker for malignant brain tumor microenvironment? Magn Reson Imaging 47:147–153. https://doi.org/10.1016/j.mri.2017.12.004 Google Scholar
- 36.Rijpkema M, Kaanders JH, Joosten FB, van der Kogel AJ, Heerschap A (2002) Effects of breathing a hyperoxic hypercapnic gas mixture on blood oxygenation and vascularity of head-and-neck tumors as measured by magnetic resonance imaging. Int J Radiat Oncol Biol Phys 53(5):1185–1191Google Scholar
- 39.Robinson SP, Rodrigues LM, Ojugo AS, McSheehy PM, Howe FA, Griffiths JR (1997) The response to carbogen breathing in experimental tumour models monitored by gradient-recalled echo magnetic resonance imaging. Br J Cancer 75(7):1000–1006Google Scholar
- 40.Griffiths JR, Taylor NJ, Howe FA, Saunders MI, Robinson SP, Hoskin PJ, Powell ME, Thoumine M, Caine LA, Baddeley H (1997) The response of human tumors to carbogen breathing, monitored by gradient-recalled echo magnetic resonance imaging. Int J Radiat Oncol Biol Phys 39(3):697–701Google Scholar
- 41.Ben Bashat D, Artzi M, Ben Ami H, Aizenstein O, Blumenthal DT, Bokstein F, Corn BW, Ram Z, Kanner AA, Lifschitz-Mercer B, Solar I, Kolatt T, Palmon M, Edrei Y, Abramovitch R (2012) Hemodynamic response imaging: a potential tool for the assessment of angiogenesis in brain tumors. PLoS One 7(11):e49416. https://doi.org/10.1371/journal.pone.0049416 Google Scholar
- 42.Karczmar GS, River JN, Li J, Vijayakumar S, Goldman Z, Lewis MZ (1994) Effects of hyperoxia on T2* and resonance frequency weighted magnetic resonance images of rodent tumours. NMR Biomed 7(1–2):3–11Google Scholar