Hypoxia positron emission tomography imaging: combining information on perfusion and tracer retention to improve hypoxia specificity

Figures & data

Figure 1. Experimental set-up and rationale for conducting the study. (A): Time series for FAZA-PET showing that in tumor-bearing mice (unlike patients), excellent hypoxia specificity is ultimately reached at late scan time points. We hypothesized that a clinical realistic intertissue and intratumoral image contrast is reached somewhere in the interval from 1 to 1.5 h PI (see section Discussion). (B): Invasive analysis confirming that late time PET scans in tumor-bearing mice are characterized by excellent hypoxia specificity (i.e., hypoxia maps are reliable). First row: Pimonidazole staining showing the distribution of pimonidazole adducts (hypoxic cells). Second row: Matching FAZA autoradiogram determined before pimonidazole staining using the same section. Last row: scatter plots showing the degree of spatial match between FAZA signal and density of hypoxic cells (segmented pimonidazole, see section Material and methods) using a pixel size of 1 mm². It is clear that the distribution of tracer largely reflects the distribution of viable hypoxic cells. FAZA: ¹⁸F-azomycin arabinoside; PET: positron emission tomography.

Figure 2. Scatterplot analysis for SCCVII. (A–C): PET images in two planes showing the time-dependent development of the intratumoral FAZA distribution in an SCCVII foot tumor. (D): whole-tumor TAC showing the distribution over time in average tumor tracer signal. (E): voxel-by-voxel correlation between late (PET_late: 160–180 min PI) and early (PET_perf: 0–10 min PI) FAZA signal. (F): voxel-by-voxel correlation between PET_late and FAZA signal 60 min PI (PET₆₀). (G): voxel-by-voxel correlation between PET_late and PET₆₀ normalized to a perfusion surrogate measure derived as the average signal from 0 to 10 min PI (PET₆₀/PET_perf). FAZA: ¹⁸F-azomycin arabinoside; PET: positron emission tomography; PI: post-injection; TAC: time–activity curve.

Figure 3. Scatterplot analysis for SiHa. (A–C): PET images in two dimensions showing the time-dependent development of the intratumoral FAZA distribution in an SiHa back tumor. (D): whole-tumor TAC showing the distribution over time in average tumor tracer signal. (E): voxel-by-voxel correlation between late (PET_late: 160–180 min PI) and early (PET_perf: 0–10 min PI) FAZA signal. (F): voxel-by-voxel correlation between PET_late and FAZA signal 60 min PI (PET₆₀). (G): voxel-by-voxel correlation between PET_late and PET₆₀ normalized to a perfusion surrogate measure derived as the average signal from 0 to 10 min PI (PET₆₀/PET_perf). FAZA: ¹⁸F-azomycin arabinoside; PET: positron emission tomography; PI: post-injection; TAC: time–activity curve.

Figure 4. Scatterplot analysis for PC3. (A–C): PET images in two dimensions showing the time-dependent development of the intratumoral FAZA distribution in a PC3 back tumor. (D): whole-tumor TAC showing the distribution over time in average tumor tracer signal. (E): voxel-by-voxel correlation between late (PET_late: 160–180 min PI) and early (PET_perf: 0–10 min PI) FAZA signal. (F): voxel-by-voxel correlation between PET_late and FAZA signal 60 min PI (PET₆₀). (G): voxel-by-voxel correlation between PET_late and PET₆₀ normalized to a perfusion surrogate measure derived as the average signal from 0 to 10 min PI (PET₆₀/PET_perf). FAZA: ¹⁸F-azomycin arabinoside; PET: positron emission tomography; PI: post-injection; TAC: time–activity curve.

Table 1. Pearson regression coefficients (R) for different tumor models showing the voxel-by-voxel correlation between PET images derived at different imaging time points.

	SCCVII (n = 3)			SiHa (n = 3)			PC3 (n = 3)
Animal number	1	2	3	1	2	3	1	2	3
A
0.4 mm
PETlate vs. PETperf, 0–5min	−0.08	−0.30	0.12	−0.14	−0.23	−0.02	−0.13	−0.34	−0.06
PETlate vs. PETperf	−0.20	0.13	0.21	−0.08	−0.22	0.24	−0.11	−0.33	−0.05
PETlate vs. PET60	0.80	0.86	0.91	0.57	0.51	0.58	0.50	0.37	0.59
PETlate vs. PET60/PETperf	0.64	0.65	0.60	0.50	0.59	0.41	0.44	0.51	0.43
PETlate vs. PET70	0.79	0.89	0.92	0.57	0.58	0.56	0.57	0.49	0.65
PETlate vs. PET70/PETperf	0.66	0.64	0.58	0.46	0.59	0.45	0.44	0.52	0.51
PETlate vs. PET80	0.81	0.89	0.94	0.58	0.62	0.60	0.59	0.56	0.66
PETlate vs. PET80/PETperf	0.67	0.62	0.58	0.46	0.59	0.59	0.45	0.53	0.53
B
0.8 mm
PETlate vs. PETperf	−0.20	0.13	0.21	−0.10	−0.23	0.04	−0.17	−0.42	−0.03
PETlate vs. PET60	0.75	0.84	0.91	0.57	0.55	0.57	0.51	0.31	0.61
PETlate vs. PET60/PETperf	0.66	0.64	0.60	0.49	0.53	0.35	0.47	0.57	0.42
PETlate vs. PET70	0.79	0.88	0.92	0.61	0.60	0.59	0.59	0.41	0.64
PETlate vs. PET70/PETperf	0.65	0.65	0.58	0.45	0.52	0.41	0.49	0.59	0.47
PETlate vs. PET80	0.81	0.88	0.94	0.64	0.61	0.63	0.61	0.55	0.68
PETlate vs. PET80/PETperf	0.67	0.65	0.58	0.48	0.58	0.43	0.49	0.59	0.53
C
0.8 mm, gauss blur (1.2 mm FWHM)
PETlate vs. PETperf	−0.22	0.07	0.18	−0.10	−0.22	0.19	−0.24	−0.45	0.00
PETlate vs. PET60	0.88	0.93	0.85	0.55	0.52	0.91	0.69	0.39	0.85
PETlate vs. PET60/PETperf	0.80	0.73	0.62	0.51	0.50	0.38	0.66	0.65	0.64
PETlate vs. PET70	0.92	0.96	0.90	0.61	0.62	0.92	0.82	0.51	0.85
PETlate vs. PET70/PETperf	0.76	0.72	0.63	0.55	0.58	0.48	0.66	0.67	0.66
PETlate vs. PET80	0.87	0.97	0.92	0.66	0.64	0.94	0.85	0.69	0.89
PETlate vs. PET80/PETperf	0.78	0.73	0.71	0.58	0.58	0.47	0.66	0.67	0.75

FWHM: full width at half maximum; PET: positron emission tomography.

Values are reported for individual animals (1, 2 and 3). A negative value denotes an inverse correlation. Analysis was performed using two different voxel sizes (0.4 and 0.8 mm) and without or with image smoothing (only at a voxel dimension of 0.8 mm).