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18F-EF5 PET Is Predictive of Response to Fractionated Radiotherapy in Preclinical Tumor Models.

Ali R, Apte S, Vilalta M, Subbarayan M, Miao Z, Chin FT, Graves EE - PLoS ONE (2015)

Bottom Line: We evaluated the relationship between pre-treatment positron emission tomography (PET) using the hypoxic tracer 18F-[2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3- pentafluoropropyl) acetamide] (18F-EF5) and the response of preclinical tumor models to a range of fractionated radiotherapies.Based on these results, 80 A549 tumors were subsequently grown and imaged using 18F-EF5 PET, and then treated with one, two, or four fraction radiation treatments to a total dose of 10-40 Gy.Terminal histologic analysis was performed to validate 18F-EF5 PET measures of hypoxia.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, Stanford University, Stanford, CA, United States of America.

ABSTRACT
We evaluated the relationship between pre-treatment positron emission tomography (PET) using the hypoxic tracer 18F-[2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3- pentafluoropropyl) acetamide] (18F-EF5) and the response of preclinical tumor models to a range of fractionated radiotherapies. Subcutaneous HT29, A549 and RKO tumors grown in nude mice were imaged using 18F-EF5 positron emission tomography (PET) in order to characterize the extent and heterogeneity of hypoxia in these systems. Based on these results, 80 A549 tumors were subsequently grown and imaged using 18F-EF5 PET, and then treated with one, two, or four fraction radiation treatments to a total dose of 10-40 Gy. Response was monitored by serial caliper measurements of tumor volume. Longitudinal post-treatment 18F-EF5 PET imaging was performed on a subset of tumors. Terminal histologic analysis was performed to validate 18F-EF5 PET measures of hypoxia. EF5-positive tumors responded more poorly to low dose single fraction irradiation relative to EF5-negative tumors, however both groups responded similarly to larger single fraction doses. Irradiated tumors exhibited reduced 18F-EF5 uptake one month after treatment compared to control tumors. These findings indicate that pre- treatment 18F-EF5 PET can predict the response of tumors to single fraction radiation treatment. However, increasing the number of fractions delivered abrogates the difference in response between tumors with high and low EF5 uptake pre-treatment, in agreement with traditional radiobiology.

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Related in: MedlinePlus

(A) Representative axial slices from microCT (top row), 18F-EF5 microPET (middle row), and anti-EF5 immunohistochemistry on (bottom row) of HT29, A549 and RKO subcutaneous tumors. CT image intensities represent Hounsfield Units (HU). PET images have been normalized by the mean background muscle %ID/g to yield tumor/muscle ratio (T/M) images. T on microCT and microPET images denotes tumor location. Brown stained areas in IHC images denote regions of bound EF5. (B) Scatterplot of the distribution of 18F-EF5 uptake in individual HT29, A549 and RKO subcutaneous tumors using three different metrics, T/M measured using CT-derived ROIs (T/MCT), T/M measured using PET-derived ROIs (T/MPET) and %ID/g values measured using CT-derived ROIs (%ID/gCT). (C) Scatterplot of the relationship between T/MCT for HT29, A549 and RKO tumors and their volume.
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pone.0139425.g001: (A) Representative axial slices from microCT (top row), 18F-EF5 microPET (middle row), and anti-EF5 immunohistochemistry on (bottom row) of HT29, A549 and RKO subcutaneous tumors. CT image intensities represent Hounsfield Units (HU). PET images have been normalized by the mean background muscle %ID/g to yield tumor/muscle ratio (T/M) images. T on microCT and microPET images denotes tumor location. Brown stained areas in IHC images denote regions of bound EF5. (B) Scatterplot of the distribution of 18F-EF5 uptake in individual HT29, A549 and RKO subcutaneous tumors using three different metrics, T/M measured using CT-derived ROIs (T/MCT), T/M measured using PET-derived ROIs (T/MPET) and %ID/g values measured using CT-derived ROIs (%ID/gCT). (C) Scatterplot of the relationship between T/MCT for HT29, A549 and RKO tumors and their volume.

Mentions: A total of 12 mice, 4 with subcutaneous HT29 tumors, 4 with subcutaneous A549 tumors, and 4 with subcutaneous RKO tumors, were imaged with 18F-EF5 microPET/CT. PET imaging examinations were performed using late stage tumors 4 weeks post-implantation. Representative results of microCT, 18F-EF5 microPET, and anti-EF5 immunohistochemistry studies are shown in Fig 1A. Subcutaneous tumors are clearly visible on the microCT scans. On the microPET images, the HT29 tumors were indistinguishable from the background signal, while A549 and RKO tumors were clearly visible, with RKO tumors exhibiting the greatest uptake. Anti-EF5 staining of these tumor specimens following animal sacrifice and tissue harvesting was in agreement with the in vivo findings, with 5 ± 3% of tumor regions staining positive in the HT29 tumors, 52 ± 14% positive in the A549 tumors, and 71 ± 19% positive in the RKO tumors. The tumor uptake values from this subject population are summarized in Fig 1B. HT29 tumors exhibited T/MCT and T/MPET values of approximately 1, indicating no significant uptake beyond background levels. T/MCT values for RKO tumors were approximately 2, while T/MPET values were significantly greater than 2 (mean 2.6±0.5). A549 tumors demonstrated a broad range of uptakes between these two extremes (mean T/MPET 1.8±0.7, mean T/MCT 1.4±0.5). The T/M values corresponded with tumor EF5 levels in the in vivo and IHC images. In contrast, the %ID/g values for each tumor showed an inverse correlation, with HT29 tumors exhibiting higher %ID/gCT and %ID/gPET values than RKO and A549 tumors. This was due to higher background 18F-EF5 uptake in the HT29 tumor mice, which was accounted for by the T/M measurements. Fig 1C shows the relationship between 18F-EF5 uptake and tumor volume. HT29 and A549 tumors were of similar sizes (mean volume 0.21±0.07 cm3 and 0.22±0.21 cm3 respectively), while RKO tumors were significantly larger (mean volume 0.79±0.39 cm3). The heterogeneity of EF5 uptake observed in the A549 tumors led us to utilize this model for the subsequent experiments to investigate the relationship between pre-treatment EF5 uptake and radiation response.


18F-EF5 PET Is Predictive of Response to Fractionated Radiotherapy in Preclinical Tumor Models.

Ali R, Apte S, Vilalta M, Subbarayan M, Miao Z, Chin FT, Graves EE - PLoS ONE (2015)

(A) Representative axial slices from microCT (top row), 18F-EF5 microPET (middle row), and anti-EF5 immunohistochemistry on (bottom row) of HT29, A549 and RKO subcutaneous tumors. CT image intensities represent Hounsfield Units (HU). PET images have been normalized by the mean background muscle %ID/g to yield tumor/muscle ratio (T/M) images. T on microCT and microPET images denotes tumor location. Brown stained areas in IHC images denote regions of bound EF5. (B) Scatterplot of the distribution of 18F-EF5 uptake in individual HT29, A549 and RKO subcutaneous tumors using three different metrics, T/M measured using CT-derived ROIs (T/MCT), T/M measured using PET-derived ROIs (T/MPET) and %ID/g values measured using CT-derived ROIs (%ID/gCT). (C) Scatterplot of the relationship between T/MCT for HT29, A549 and RKO tumors and their volume.
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pone.0139425.g001: (A) Representative axial slices from microCT (top row), 18F-EF5 microPET (middle row), and anti-EF5 immunohistochemistry on (bottom row) of HT29, A549 and RKO subcutaneous tumors. CT image intensities represent Hounsfield Units (HU). PET images have been normalized by the mean background muscle %ID/g to yield tumor/muscle ratio (T/M) images. T on microCT and microPET images denotes tumor location. Brown stained areas in IHC images denote regions of bound EF5. (B) Scatterplot of the distribution of 18F-EF5 uptake in individual HT29, A549 and RKO subcutaneous tumors using three different metrics, T/M measured using CT-derived ROIs (T/MCT), T/M measured using PET-derived ROIs (T/MPET) and %ID/g values measured using CT-derived ROIs (%ID/gCT). (C) Scatterplot of the relationship between T/MCT for HT29, A549 and RKO tumors and their volume.
Mentions: A total of 12 mice, 4 with subcutaneous HT29 tumors, 4 with subcutaneous A549 tumors, and 4 with subcutaneous RKO tumors, were imaged with 18F-EF5 microPET/CT. PET imaging examinations were performed using late stage tumors 4 weeks post-implantation. Representative results of microCT, 18F-EF5 microPET, and anti-EF5 immunohistochemistry studies are shown in Fig 1A. Subcutaneous tumors are clearly visible on the microCT scans. On the microPET images, the HT29 tumors were indistinguishable from the background signal, while A549 and RKO tumors were clearly visible, with RKO tumors exhibiting the greatest uptake. Anti-EF5 staining of these tumor specimens following animal sacrifice and tissue harvesting was in agreement with the in vivo findings, with 5 ± 3% of tumor regions staining positive in the HT29 tumors, 52 ± 14% positive in the A549 tumors, and 71 ± 19% positive in the RKO tumors. The tumor uptake values from this subject population are summarized in Fig 1B. HT29 tumors exhibited T/MCT and T/MPET values of approximately 1, indicating no significant uptake beyond background levels. T/MCT values for RKO tumors were approximately 2, while T/MPET values were significantly greater than 2 (mean 2.6±0.5). A549 tumors demonstrated a broad range of uptakes between these two extremes (mean T/MPET 1.8±0.7, mean T/MCT 1.4±0.5). The T/M values corresponded with tumor EF5 levels in the in vivo and IHC images. In contrast, the %ID/g values for each tumor showed an inverse correlation, with HT29 tumors exhibiting higher %ID/gCT and %ID/gPET values than RKO and A549 tumors. This was due to higher background 18F-EF5 uptake in the HT29 tumor mice, which was accounted for by the T/M measurements. Fig 1C shows the relationship between 18F-EF5 uptake and tumor volume. HT29 and A549 tumors were of similar sizes (mean volume 0.21±0.07 cm3 and 0.22±0.21 cm3 respectively), while RKO tumors were significantly larger (mean volume 0.79±0.39 cm3). The heterogeneity of EF5 uptake observed in the A549 tumors led us to utilize this model for the subsequent experiments to investigate the relationship between pre-treatment EF5 uptake and radiation response.

Bottom Line: We evaluated the relationship between pre-treatment positron emission tomography (PET) using the hypoxic tracer 18F-[2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3- pentafluoropropyl) acetamide] (18F-EF5) and the response of preclinical tumor models to a range of fractionated radiotherapies.Based on these results, 80 A549 tumors were subsequently grown and imaged using 18F-EF5 PET, and then treated with one, two, or four fraction radiation treatments to a total dose of 10-40 Gy.Terminal histologic analysis was performed to validate 18F-EF5 PET measures of hypoxia.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, Stanford University, Stanford, CA, United States of America.

ABSTRACT
We evaluated the relationship between pre-treatment positron emission tomography (PET) using the hypoxic tracer 18F-[2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3- pentafluoropropyl) acetamide] (18F-EF5) and the response of preclinical tumor models to a range of fractionated radiotherapies. Subcutaneous HT29, A549 and RKO tumors grown in nude mice were imaged using 18F-EF5 positron emission tomography (PET) in order to characterize the extent and heterogeneity of hypoxia in these systems. Based on these results, 80 A549 tumors were subsequently grown and imaged using 18F-EF5 PET, and then treated with one, two, or four fraction radiation treatments to a total dose of 10-40 Gy. Response was monitored by serial caliper measurements of tumor volume. Longitudinal post-treatment 18F-EF5 PET imaging was performed on a subset of tumors. Terminal histologic analysis was performed to validate 18F-EF5 PET measures of hypoxia. EF5-positive tumors responded more poorly to low dose single fraction irradiation relative to EF5-negative tumors, however both groups responded similarly to larger single fraction doses. Irradiated tumors exhibited reduced 18F-EF5 uptake one month after treatment compared to control tumors. These findings indicate that pre- treatment 18F-EF5 PET can predict the response of tumors to single fraction radiation treatment. However, increasing the number of fractions delivered abrogates the difference in response between tumors with high and low EF5 uptake pre-treatment, in agreement with traditional radiobiology.

No MeSH data available.


Related in: MedlinePlus