1.
Tumor hypoxia is associated with aggressive phenotypes,
notably influencing angiogenesis, metastasis, and response to therapy.
Therefore, the ability to identify hypoxia could allow stratification for
optimized therapy.
2.
MRI methods have been developed to quantify pO2,
and hence tumor hypoxia, or provide pertinent surrogate biomarkers.
3.
This presentation will consider opportunities and
applications for patients in the context of competing technologies.
4.
Virtues and
shortcomings of diverse techniques will be considered in terms of ease of
implementation, nature of observations (spatial resolution, precision,
dynamics, and need for exogenous reporter agents) and validity and robustness
of measurements.
5.
Examples will be drawn from recent studies in human, focusing
on our own experience.
Historically,
radiology has served to identify tumors in terms of location, size and
metastatic spread. Specific acquisition sequences such as T2-weighting
may enhance tumor delineation. Contrast agents enhance sensitivity and
specificity based on relative vascular permeability and agent retention. Metastatic
spread is probably best revealed by FDG-PET. A new paradigm is personalized
oncology based on the unique characteristics of the individual tumors. Crucial goals
are predicting the optimal therapy and providing early indications of
therapeutic efficacy. Several parameters are considered pertinent, since they
seem to differ in tumors versus normal tissue: notably, vascular perfusion, pH
and oxygenation. Tumors are often characterized by convoluted, disorganized
vascular networks providing inefficient blood flow and nutrient supply. The
direct consequence is often hypoxia and this may lead to elevated glycolysis,
and hence, acidosis. These parameters are interrelated and may provide insights
into tumor aggressiveness and optimal therapy.
The most widespread assessment of tumor
pathophysiology has been based DCE-MRI with thousands of studies reported using
various levels of analytical sophistication (1-3). Dynamic
contrast curves have been related to the stage of breast cancer, though there
remains discussion of the optimal technique with trade-offs between spatial and
temporal resolution and quantitative versus qualitative analysis (4-6). In
prostate, indications of texture analysis based on differential enhancement
curves appear valuable to delineate tumors and integration of multiparametric
imaging is showing promise (7-9). Several
studies have indicated the DCE-MRI may be related tumor hypoxia, e.g., correlations with polarographic
oxygen electrodes in human cervical cancer (10). Various supporting studies have been reported in
diverse melanoma and tumor models by the group of Rofstad (11, 12). We
recently found the strong correlation between the parameter ve
and time for rat prostate tumors to quadruple in volume following single
high-dose radiation (essentially SBRT) (13). DCE-MRI is attractive, since it is routine in the
clinic, but there is a major emphasis on developing methods more directly
related to tumor oxygenation.
The
oxygen molecule is paramagnetic and enhances spin-lattice relaxation (14). In saline R1=f(pO2).
It has been exploited to measure pO2 in various human body fluids in situ, where the composition is
well-characterized and homogenous, e.g.,
urine (15), CSF (16) and vitreous humor (17). Other factors such as ions, protein
concentration, and pH can influence R1 and it is not expected to
directly to reflect pO2 in tissues in vivo. However, a change in R1 accompanying an
intervention such as hyperoxic gas challenge should reflect a variation in pO2
(ΔR1=f(ΔpO2)). Several investigations have demonstrated such
changes in both pre-clinical and human research studies. Many studies have
examined changes in T1-weighted signal reflecting a variation in R1,
but increasingly quantitative R1 maps are presented. In 1996,
Edelman et al., reported oxygen
enhanced MRI of human lung in response to an oxygen breathing challenge and they
observed differential regional ventilation (18). They noted that the
relaxivity of oxygen is small, but found substantial changes attributed to the
large alveolar surface area. Super oxygen-saturated water has been explored for
GI contrast (19).
Tumors
are more complex and it should be noted that changes in hemoglobin
concentration and pH can influence R1 and flow may alter apparent R1.
Howe et al., noted T1-weighted
signal response in tumors accompanying a carbogen breathing challenge (20). However, the
changes were generally small and subtle, compared to BOLD response (discussed
below) and were therefore largely neglected. In 2001, Matsumoto et al., showed a significant response in
R1 to hyperbaric oxygen challenge in tumors and suggested the
acronym TOLD (tissue oxygen level dependent) contrast by analogy to BOLD (21). This work ignited
interest from several groups. Notably, O’Connor et al. explored both human applications and pre-clinical tests (22-26). They demonstrated R1
response in normal human organs in response to oxygen breathing challenge and
in pre-clinical studies of human tumors. Correlations were determined with
hypoxia based on immunohistochemistry (27). Most recently, they
showed that correlation of R1 and pimonidazole defined hypoxia was
improved in some tumor types by including a DCE-MRI scan to define non-perfused
regions (22).
We have examined TOLD extensively in Dunning prostate
rat tumors and found responses consistent with BOLD and quantitative 19F
MRI oximetry in many tumors (Fig. 1) (31, 32). Moreover,
we found that tumor growth delay (time to quadruple in volume, T4)
following single high dose irradiation (30 Gray) was related to TOLD response
(but not BOLD) (31). Specifically, those tumors showing a large TOLD (ΔSI
or ΔR1) response to an oxygen breathing challenge prior to
irradiation, showed a significantly greater tumor growth delay (Fig. 1). In
common with most pre-clinical investigations, our initial investigations
examined subcutaneous tumors, but we have recently demonstrated TOLD in orthotopic
rat prostate tumors also (Fig. 1E) and have recently demonstrated R1
response to oxygen breathing challenge in human prostate cancer. Oxygen
challenge was added to the standard pre-surgical treatment planning and
compliance was excellent.
To
date, BOLD assessment of tumors has been far more popular with human studies
presented at several disease sites (34) including breast (Fig. 2) (35, 36), cervix (37, 38) (Fig. 3), prostate (39, 40), kidney (41, 42), head and neck (43), brain (44, 45) and lung (Fig. 4). R2* is
strongly influenced by the concentration of deoxyhemoglobin, as exploited in
fMRI of neuronal activation (46). Extensive studies
from Griffiths, Howe, Robinson et al.
showed differential BOLD response to oxygen breathing challenge and the
magnitude could be related to vascular extent (20, 47-50). Many studies have used
semi-quantitative measurements based on %ΔSI though this may be influenced by
flow effects, as presented in the FLOOD concept (20). Several studies
have examined correlations of quantitative oximetry (pO2) with BOLD
and general trends are widely reported, but the magnitude of response may be
highly variable (51-53). We found that a BOLD signal response to
oxygen breathing challenge greater than 3% in 13762NF rat breast tumors
coincided with elimination of hypoxia (52). However, specific
inconsistencies have been noted, e.g.,
increased BOLD signal following sacrifice has been attributed to pressure
induced vascular collapse post mortem and hence decreased concentration of
deoxyhemoglobin (47). Gallez et al., also reported discrepancies with
respect to pharmacological interventions (54).
Many human investigations have focused on proof of
principle demonstrating that BOLD is feasible in human tumors. Baseline R2*
values were related to human prostate tumor hypoxia (55). Rijpkema el
al. examined BOLD changes in head and neck tumors in connection with the
ARCON therapeutic trial (43). We found that women whose breast tumors showed a
large BOLD response to oxygen breathing challenge prior to therapy had a complete
radiological and pathological response following adjutant chemotherapy for
locally advanced breast cancer whereas those with small BOLD showed at best
stable disease (35) (Fig. 2).
As
noted, BOLD and TOLD have been related to tumor oxygenation. We favor combining
the approaches particularly for the assessment of tumor oxygenation with
respect to respiratory gas challenge and have proposed the acronym DOCENT (Dynamic Oxygen Challenge
evaluated by NMR T1 and T2*) (56). Specifically, BOLD
is sensitive to vascular delivery, but does not necessarily indicate change in
pO2. Meanwhile, TOLD is more closely related to pO2, but
the magnitude of response tends to be much smaller (Fig. 1). A dynamic
combination is technically feasible emphasizing the larger BOLD effect confirmed
by TOLD. As expected, TOLD response is usually temporarily delayed compared
with BOLD, since oxygen is first delivered in the vasculature and must then
diffuse into tissues. In both pre-clinical and human studies, we generally perform
a baseline R1 map followed by interleaved R2* and T1-weighted
images to reveal dynamic changes and finally another R1 map.
In
both Dunning prostate R3327-AT1 and -HI tumors, we found a close correlation
between semi-quantitative T1- and T2*-weighted signal
response to oxygen breathing challenge, but BOLD was generally three times greater
(32). Intriguingly, while
the well vascularized HI tumors also showed a correlation between mean ΔR1
and ΔR2*, this was noticeably absent for AT1 tumors (32). Voxel-by-voxel
analysis showed very diverse responses including matched and unmatched behavior.
Remmele et al., similarly reported
matched and unmatched responses in human brain tumors and proposed the
following rationale (29). In regions that are well oxygenated, excess dissolved
oxygen will increase the plasma and tissue fluid R1, but will have
negligible effect on hemoglobin (Hb) saturation (hence, small effect on R2*).
Meanwhile, hypoxic regions with suboptimal oxygen saturation will show
preferential binding of excess oxygen molecules to deoxygenated Hb molecules,
which reduces the content of paramagnetic deoxyHb, shortening both R2*
and R1. In the absence of deoxyHb (e.g., fluids like in cystic tumor regions or edema), the excess
oxygen in solution prolongs both R1 and R2*. Non-oxygenation-related
R2* increase and R1 decrease, potentially related to
vascular steal.
Comparison of BOLD and TOLD effects in tumors has been
reported for various species including mice (57, 58),
rats (31, 32),
rabbits (59) and man (24, 30). O’Connor
et al. noted distinctly different
BOLD and TOLD effects in certain normal organs, as we have also observed (Fig.
5) (24, 30, 60).
Recognizing
the greater solubility of oxygen in lipids as compared with water, Gallez
(Mapping of Oxygen By Imaging Lipids relaxation
Enhancement) (61). They specifically showed that changes in lipid
relaxation were greater than water: about 2 and 11 fold greater for the
resonances at 1.2 and 4 ppm, respectively. Observations were reported in mice,
with respect to ischemia, liver steatosis, and tumors (62). This
method requires effective water suppression, but pilot studies have also been
reported in human volunteers (63).
. (64) demonstrated that a
multi parametric analysis of tumor water signal could directly provide
estimates of pO
. Specifically, biexponential analysis of IVIM
(Intra Voxel Incoherent Motion) allowed estimation of tumor vascular volume;
then in combination with R
F MRI of PFC. The
current measurements are limited to air breathing due to model assumptions, but
can provide an effective quantitative baseline maps from which to evaluate BOLD
and TOLD responses to interventions. To date measurements have been limited to
rat tumors and calculations will need to be modified for other species due to
differences in hematocrit and oxygen-hemoglobin binding constants.
Oncologists and patients increasingly have choice of
many potentially effective therapies.
However, the optimal intervention may depend on unique characteristics
of a specific tumor; hence the desire for precision oncology. Hypoxia has a
significant role in tumor aggressiveness and response to therapy and therefore
the ability to measure tumor oxygenation and dynamic response interventions
could play a significant role in treatment. Hypoxia may justify a radiation
boost potentially with local dose painting based on intensity modulated
radiotherapy or selection of alternant ionizing beams, such as proton or carbon
and inclusion of hypoxic cell selective cytotoxins. As presented, there are
several NMR approaches to assessing tumor oxygenation. Examples have been
demonstrated in pre-clinical models and increasingly are being evaluated for
effective translation to humans, but it remains to be seen which will be most
effective in terms of robust prognostic imaging biomarkers offering useful sensitivity
and specificity. Further relevant discussion is provided in the companion tutorial
on Tumor Hypoxia Imaging (#7138).
References
1. Sourbron,
S. P., and Buckley, D. L. Classic models for dynamic contrast-enhanced MRI. NMR Biomed 2013; 26, 1004-1027.
2. Zollner, F. G.,
Daab, M., Sourbron, S. P., Schad, L. R., Schoenberg, S. O., and Weisser, G. An
open source software for analysis of dynamic contrast enhanced magnetic
resonance images: UMMPerfusion revisited. BMC
medical imaging 2016; 16, 7.
3. Cao, Y. The promise
of dynamic contrast-enhanced imaging in radiation therapy. Semin Radiat Oncol 2011; 21,
147-156.
4. Knopp, M. V.,
Weiss, E., Sinn, H. P., Mattern, J., Junkermann, H., Radeleff, J., Magener, A.,
Brix, G., Delorme, S., Zuna, I., and van Kaick, G. Pathophysiologic basis of
contrast enhancement in breast tumors. J.
Magn. Reson. Imaging 1999; 10,
260-266.
5. Kuhl, C. K. Current
status of breast MR imaging - Part 2. Clinical applications. Radiology 2007; 244, 672-691.
6. Hylton, N. Dynamic
contrast-enhanced magnetic resonance imaging as an imaging biomarker. J. Clin. Oncol. 2006; 24, 3293-3298.
7. Costa, D. N.,
Lotan, Y., Rofsky, N. M., Roehrborn, C., Liu, A., Hornberger, B., Xi, Y.,
Francis, F., and Pedrosa, I. Assessment of Prospectively Assigned Likert Scores
for Targeted Magnetic Resonance Imaging-Transrectal Ultrasound Fusion Biopsies
in Patients with Suspected Prostate Cancer. J.
Urol. 2016; 195, 80-87.
8. Oto, A., Yang, C.,
Kayhan, A., Tretiakova, M., Antic, T., Schmid-Tannwald, C., Eggener, S.,
Karczmar, G. S., and Stadler, W. M. Diffusion-Weighted and Dynamic
Contrast-Enhanced MRI of Prostate Cancer: Correlation of Quantitative MR
Parameters With Gleason Score and Tumor Angiogenesis. Am. J. Roentgenol. 2011; 197,
1382-1390.
9. Alonzi, R., Taylor,
N. J., Stirling, J. J., d'Arcy, J. A., Collins, D. J., Saunders, M. I., Hoskin,
P. J., and Padhani, A. R. Reproducibility and Correlation Between Quantitative
and Semiquantitative Dynamic and Intrinsic Susceptibility-Weighted MRI
Parameters in the Benign and Malignant Human Prostate. J. Magn. Reson. Imaging 2010; 32,
155-164.
10. Loncaster, J. A.,
Carrington, B. M., Sykes, J. R., Jones, A. P., Todd, S. M., Cooper, R.,
Buckley, D. L., Davidson, S. E., Logue, J. P., Hunter, R. D., and West, C. M.
L. Prediction of radiotherapy outcome using dynamic contrast enhanced MRI of
carcinoma of the cervix. Int. J. Radiat.
Oncol. Biol. Phys. 2002; 54,
759-767.
11. Egeland, T. A. M.,
Gulliksrud, K., Gaustad, J. V., Mathiesen, B., and Rofstad, E. K. Dynamic contrast-enhanced-MRI
of tumor hypoxia. Magn. Reson. Med.
2012; 67, 519-530.
12. Ovrebo, K. M.,
Hompland, T., Mathiesen, B., and Rofstad, E. K. Assessment of hypoxia and
radiation response in intramuscular experimental tumors by dynamic
contrast-enhanced magnetic resonance imaging. Radiother. Oncol. 2012; 102,
429-435.
13. Hallac, R., Zhou, H., Pidikiti, R.,
Song, K., Stojadinovic, S., Zhao, D., Kodibagkar, V., Peschke, P., Solberg, T.,
and R.P., M. A role for DCE MRI in predicting tumor radiation response. In Proc. Joint Annual Meeting ISMRM-ESMRMB,
Milan, Italy (2014.)
14. Chiarotti, G.,
Cristiani, G., and Giulotto, L. Proton relaxation in pure liquids and in
liquids containing paramagnetic gases in solution. Nuovo Cimento 1955; 1,
863-873.
15. Wang, Z. J., Joe,
B. N., Coakley, F. V., Zaharchuk, G., Busse, R., and Yeh, B. M. Urinary Oxygen
Tension Measurement in Humans Using Magnetic Resonance Imaging. Acad Radiol. 2008; 15, 1467-1473.
16. Zaharchuk, G.,
Martin, A. J., Rosenthal, G., Manley, G. T., and Dillon, W. P. Measurement of
cerebrospinal fluid oxygen partial pressure in humans using MRI. Magn. Reson. Med. 2005; 54, 113-121.
17. Berkowitz, B. A.,
McDonald, C., Ito, Y., Tofts, P. S., Latif, Z., and Gross, J. Measuring the
human retinal oxygenation response to a hyperoxic challenge using MRI:
Eliminating blinking artifacts and demonstrating proof of concept. Magn. Reson. Med. 2001; 46, 412-416.
18. Edelman, R. R.,
Hatabu, H., Tadamura, E., Li, W., and Prasad, P. V. Noninvasive assessment of
regional ventilation in the human lung using oxygen-enhanced magnetic resonance
imaging. Nature Medicine 1996; 2, 1236-1239.
19. Nestle, N.,
Wunderlich, A., and Nüssle-Kügele, K. In vivo observation of
oxygen-supersaturated water in the human mouth and stomach. Magn. Reson. Imaging 2004; 22, 551-556.
20. Howe, F. A.,
Robinson, S. P., Rodrigues, L. M., and Griffiths, J. R. Flow and oxygenation
dependent (FLOOD) contrast MR imaging to monitor the response of rat tumors to
carbogen breathing. Magn. Reson. Imaging
1999; 17, 1307-1318.
21. Matsumoto, K.,
Bernardo, M., Subramanian, S., Choyke, P., Mitchell, J. B., Krishna, M. C., and
Lizak, M. J. MR assessment of changes of tumor in response to hyperbaric oxygen
treatment. Magn. Reson. Med. 2006; 56, 240-246.
22. O'Connor, J. P. B.,
Boult, J. K., Jamin, Y., Babur, M., Finegan, K. G., Williams, K. J., Little, R.
A., Jackson, A., Parker, G. J. M., Reynolds, A. R., Waterton, J. C., and
Robinson, S. P. Oxygen enhanced MRI accurately identifies, quantifies, and maps
hypoxia in preclinical cancer models. Cancer
Res. 2015;
23. O'Connor, J. P. B.,
Jackson, A., Buonaccorsi, G. A., Buckley, D. L., Roberts, C., Watson, Y.,
Cheung, S., McGrath, D. M., Naish, J. H., Rose, C. J., Dark, P. M., Jayson, G.
C., and Parker, G. J. M. Organ-specific effects of oxygen and carbogen gas
inhalation on tissue longitudinal relaxation times. Magn. Reson. Med. 2007; 58,
490-496.
24. O'Connor, J. P. B.,
Naish, J. H., Jackson, A., Waterton, J. C., Watson, Y., Cheung, S., Buckley, D.
L., McGrath, D. M., Buonaccorsi, G. A., Mills, S. J., Roberts, C., Jayson, G.
C., and Parker, G. J. M. Comparison of Normal Tissue R-1 and R-2* Modulation by
Oxygen and Carbogen. Magn. Reson. Med.
2009; 61, 75-83.
25. O'Connor, J. P. B.,
Naish, J. H., Parker, G. J. M., Waterton, J. C., Watson, Y., Jayson, G. C.,
Buonaccorsi, G. A., Cheung, S., Buckley, D. L., McGrath, D. M., West, C. M. L.,
Davidson, S. E., Roberts, C., Mills, S. J., Mitchell, C. L., Hope, L., Ton, C.,
and Jackson, A. Preliminary Study of Oxygen-Enhanced Longitudinal Relaxation in
MRI: a Potential Novel Biomarker of Oxygenation Changes in Solid Tumors. Int. J. Radiat. Oncol. Biol. Phys. 2009;
75, 1209-1215.
26. O'Connor, J. P. B.,
Rose, C. J., Waterton, J. C., Carano, R. A. D., Parker, G. J. M., and Jackson,
A. Imaging Intratumor Heterogeneity: Role in Therapy Response, Resistance, and
Clinical Outcome. Clinical Cancer
Research 2015; 21, 249-257.
27. Linnik, I. V.,
Scott, M. L. J., Holliday, K. F., Woodhouse, N., Waterton, J. C., O'Connor, J.
P. B., Barjat, H., Liess, C., Ulloa, J., Young, H., Dive, C., Hodgkinson, C.
L., Ward, T., Roberts, D., Mills, S. J., Thompson, G., Buonaccorsi, G. A.,
Cheung, S., Jackson, A., Naish, J. H., and Parker, G. J. M. Noninvasive tumor
hypoxia measurement using magnetic resonance imaging in murine U87 glioma
xenografts and in patients with glioblastoma. Magn. Reson. Med. 2014; 71,
1854-1862.
28. Beeman, S. C.,
Shui, Y.-B., Perez-Torres, C. J., Engelbach, J. A., Ackerman, J. J. H., and
Garbow, J. R. O2-sensitive MRI distinguishes brain tumor versus radiation
necrosis in murine models. Magn. Reson.
Med. 2015; n/a-n/a.
29. Remmele, S., Mason, R. P., and
O’Connor, J. B. P. (2014) MRI Hypoxia Measurements. In Functional Imaging in Oncology (Luna, A., ed), Springer-Verlag,
Heidelberg
30. Remmele, S.,
Sprinkart, A. M., Muller, A., Traber, F., von Lehe, M., Gieseke, J., Flacke,
S., Willinek, W. A., Schild, H. H., Senegas, J., Keupp, J., and Murtz, P.
Dynamic and simultaneous MR measurement of R1 and R2*changes during respiratory
challenges for the assessment of blood and tissue oxygenation. Magn. Reson. Med. 2013; 70, 136-146.
31. Hallac, R. R.,
Zhou, H., Pidikiti, R., Song, K., Stojadinovic, S., Zhao, D., Solberg, T.,
Peschke, P., and Mason, R. P. Correlations of noninvasive BOLD and TOLD MRI
with pO2 and relevance to tumor radiation response. Magn. Reson. Med. 2014; 71, 1863-1873.
32. Zhao, D.,
Pacheco-Torres, J., Hallac, R. R., White, D., Peschke, P., Cerdán, S., and
Mason, R. P. Dynamic oxygen challenge evaluated by NMR T1 and T2*
– insights into tumor oxygenation. NMR Biomed. 2015; 28, 937–947.
33. Zhou, H., Wilson, D., Lickliter, J.,
Ruben, J., Raghunand, N., Sellenger, M., Mason, R. P., and Unger, E. TOLD MRI
Validation of Reversal of Tumor Hypoxia in Glioblastoma with a Novel Oxygen
Therapeutic. In ISMRM, Singapore (2016)
34. Taylor, N. J.,
Baddeley, H., Goodchild, K. A., Powell, M. E. B., Thoumine, M., Culver, L. A.,
Stirling, J. J., Saunders, M. I., Hoskin, P. J., Phillips, H., Padhani, A. R.,
and Griffiths, J. R. BOLD MRI of human tumor oxygenation during carbogen
breathing. J. Magn. Reson. Imaging
2001; 14, 156-163.
35. Jiang, L.,
Weatherall, P. T., McColl, R. W., Tripathy, D., and Mason, R. P. Blood
oxygenation level-dependent (BOLD) contrast magnetic resonance imaging (MRI)
for prediction of breast cancer chemotherapy response: A pilot study. J. Magn. Reson. Imaging 2013; 37, 1083–1092.
36. Rakow-Penner, R.,
Daniel, B., and Glover, G. H. Detecting Blood Oxygen Level-Dependent (BOLD)
Contrast in the Breast. J. Magn. Reson.
Imaging 2010; 32, 120-129.
37. Hallac, R. R.,
Ding, Y., Yuan, Q., McColl, R. W., Lea, J., Sims, R. D., Weatherall, P. T., and
Mason, R. P. Oxygenation in cervical cancer and normal uterine cervix assessed
using blood oxygenation level-dependent (BOLD) MRI at 3T. NMR Biomed 2012; 25,
1321–1330.
38. Li, X. S., Fan, H.
X., Fang, H., Song, Y. L., and Zhou, C. W. Value of R2*obtained from
T2*-weighted imaging in predicting the prognosis of advanced cervical squamous
carcinoma treated with concurrent chemoradiotherapy. JMRI 2015; 42, 681-688.
39. Diergarten, T.,
Martirosian, P., Kottke, R., Vogel, U., Stenzl, A., Claussen, C. D., and
Schlemmer, H. P. Functional characterization of prostate cancer by integrated
magnetic resonance imaging and oxygenation changes during carbogen breathing. Invest. Radiol. 2005; 40, 102-109.
40. Alonzi, R.,
Padhani, A. R., Maxwell, R. J., Taylor, N. J., Stirling, J. J., Wilson, J. I.,
d'Arcy, J. A., Collins, D. J., Saunders, M. I., and Hoskin, P. J. Carbogen
breathing increases prostate cancer oxygenation: a translational MRI study in
murine xenografts and humans. Br J Cancer
2009; 100, 644-648.
41. Min, J. H., Kim, C.
K., Park, B. K., Kim, E., and Kim, B. Assessment of Renal Lesions With Blood
Oxygenation Level-Dependent MRI at 3 T: Preliminary Experience. Am. J. Roentgenol. 197, W489-W494.
42. Wu, G. Y., Suo, S.
T., Lu, Q., Zhang, J., Zhu, W. Q., and Xu, J. R. The Value of Blood Oxygenation
Level-Dependent (BOLD) MR Imaging in Differentiation of Renal Solid Mass and
Grading of Renal Cell Carcinoma (RCC): Analysis Based on the Largest
Cross-Sectional Area versus the Entire Whole Tumour. Plos One 2015; 10, 11.
43. Rijpkema, M.,
Kaanders, J. H., Joosten, F. B., van der Kogel, A. J., and Heerschap, A.
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. 2002; 53, 1185-1191.
44. Mürtz, P., Flacke,
S., Müller, A., Soehle, M., Wenningmann, I., Kovacs, A., Träber, F., Willinek,
W. A., Gieseke, J., Schild, H. H., and Remmele, S. Changes in the MR relaxation
rate R2* induced by respiratory challenges at 3.0 T: a comparison of two
quantification methods. NMR Biomed. 2010; 23, 1053-1060.
45. Yetkin, F. Z., and
Mendelsohn, D. Hypoxia imaging in brain tumors. Neuroimag. Clin. North Am. 2002; 12, 537-+.
46. Ogawa, S., Lee, T.
M., Kay, A. R., and Tank, D. W. Brain magnetic resonance imaging with contrast
dependent on blood oxygenation. Proc.
Natl. Acad. Sci. (USA) 1990; 87,
9868-9872.
47. Howe, F. A., Robinson,
S. P., McIntyre, D. J. O., Stubbs, M., and Griffiths, J. R. Issues in flow and
oxygenation dependent contrast (FLOOD) imaging of tumours. NMR Biomed. 2001; 14,
497-506.
48. Griffiths, J. R.,
Taylor, N. J., Howe, F. A., Saunders, M. I., Robinson, S. P., Hoskins, P. J.,
Powell, M. E. B., Thoumine, M., Caine, L. A., and Baddeley, H. The response of
human tumors to carbogen breathing monitored by gradient-recalled echo MRI. Int. J. Radiat. Oncol. Biol. Phys. 1997;
39, 697-701.
49. Robinson, S. P.,
Howe, F. A., Rodrigues, L. M., Stubbs, M., and Griffiths, J. R. Magnetic
resonance imaging techniques for monitoring changes in tumor oxygenation and
blood flow. Semin. Radiat. Oncol.
1998; 8, 198-207.
50. Robinson, S. P.,
Rijken, P., Howe, F. A., McSheehy, P. M. J., van der Sanden, B. P. J.,
Heerschap, A., Stubbs, M., van der Kogel, A. J., and Griffiths, J. R. Tumor
vascular architecture and function evaluated by non-invasive susceptibility MRI
methods and immunohistochemistry. J.
Magn. Reson. Imaging 2003; 17, 445-454.
51. Baudelet, C., and
Gallez, B. How does blood oxygen level-dependent (BOLD) contrast correlate with
oxygen partial pressure (pO2) inside tumors? Magn. Reson. Med. 2002; 48,
980-986.
52. Zhao, D., Jiang,
L., Hahn, E. W., and Mason, R. P. Comparison of 1H blood oxygen
level-dependent (BOLD) and 19F MRI to investigate tumor oxygenation.
Magn. Reson. Med. 2009; 62, 357-364.
53. Al-Hallaq, H. A.,
River, J. N., Zamora, M., Oikawa, H., and Karczmar, G. S. Correlation of
magnetic resonance and oxygen microelectrode measurements of carbogen-induced
changes in tumor oxygenation. Int. J.
Radiat. Oncol. Biol. Phys. 1998; 41,
151-159.
54. Jordan, B. F.,
Crokart, N., Baudelet, C., Cron, G. O., Ansiaux, R., and Gallez, B. Complex
relationship between changes in oxygenation status and changes in R-2(*): The
case of insulin and NS-398, two inhibitors of oxygen consumption. Magn. Reson. Med. 2006; 56, 637-643.
55. Chopra, S., Foltz,
W. D., Milosevic, M. F., Toi, A., Bristow, R. G., Menard, C., and Haider, M. A.
Comparing oxygen-sensitive MRI (BOLD R2*) with oxygen electrode
measurements: A pilot study in men with prostate cancer. Int. J. Radiat. Biol. 2009; 85,
805 - 813.
56. Pacheco-Torres, J., Zhao, D., Contero,
A., Peschke, P., and Mason, R. P. DOCENT- Dynamic Oxygen Challenge Evaluated by
NMR T1 and T2* of Tumors. . In 16th ISMRM p. 450, Toronto, Canada (2008)
57. Peller, M.,
Weissfloch, L., Stehling, M. K., Weber, J., Bruening, R.,
Senekowitsch-Schmidtke, R., Molls, M., and Reiser, M. Oxygen-induced MR signal
changes in murine tumors. Magnetic
Resonance Imaging 1998; 16,
799-809.
58. Burrell, J. S.,
Walker-Samuel, S., Baker, L. C. J., Boult, J. K. R., Jamin, Y., Halliday, J.,
Waterton, J. C., and Robinson, S. P. Exploring ΔR2* and ΔR1
as imaging biomarkers of tumor oxygenation. J.
Magn. Reson. Imaging 2013; 38,
429-434.
59. Winter, J. D.,
Akens, M. K., and Cheng, H.-L. M. Quantitative MRI assessment of VX2 tumour
oxygenation changes in response to hyperoxia and hypercapnia. Phys. Med. Biol. 2011; 56, 1225.
60. Ding, Y., Mason, R.
P., McColl, R. W., Yuan, Q., Hallac, R. R., Sims, R. D., and Weatherall, P. T.
Simultaneous measurement of tissue oxygen level-dependent (TOLD) and blood
oxygenation level-dependent (BOLD) effects in abdominal tissue oxygenation
level studies. J. Magn. Reson. Imaging
2013; 38, 1230-1236.
61. Jordan, B. F.,
Magat, J., Colliez, F., Ozel, E., Fruytier, A.-C., Marchand, V., Mignion, L.,
Bouzin, C., Cani, P. D., Vandeputte, C., Feron, O., Delzenne, N., Himmelreich,
U., Denolin, V., Duprez, T., and Gallez, B. Mapping of oxygen by imaging lipids
relaxation enhancement: A potential sensitive endogenous MRI contrast to map
variations in tissue oxygenation. Magn.
Reson. Med. 2013; 70, 732-744.
62. Colliez, F., Neveu,
M. A., Magat, J., Pham, T. T. C., Gallez, B., and Jordan, B. F. Qualification
of a Noninvasive Magnetic Resonance Imaging Biomarker to Assess Tumor
Oxygenation. Clinical Cancer Research
2014; 20, 5403-5411.
63. Safronova, M. M.,
Colliez, F., Magat, J., Joudiou, N., Jordan, B. F., Raftopoulos, C., Gallez,
B., and Duprez, T. Mapping of global R1 and R2*values versus lipids R1 values
as potential markers of hypoxia in human glial tumors: A feasibility study. Magnetic Resonance Imaging 2016; 34, 105-113.
64. Zhang, Z., Hallac,
R. R., Peschke, P., and Mason, R. P. A noninvasive tumor oxygenation imaging
strategy using magnetic resonance imaging of endogenous blood and tissue water.
Magn. Reson. Med. 2014; 71, 561-569.