Purpose: Mild hyperthermia can improve tumour oxygenation and enhance radiosensitivity. Imaging the hypoxic fraction of a tumour can guide hyperthermia treatment planning and facilitate treatment optimization. 64Cu-ATSM (Copper-diacetyl-bis(N4-methylthiosemicarbazone)) is a positron emitting compound that has been demonstrated to have rapid uptake and selective retention in hypoxic cells and has been used for imaging human and animal tumours. The purpose of the present report is to establish methodology that will allow one to use Cu-ATSM PET scanning to detect the impact of hyperthermia on tumour physiology in as little time as possible.Materials and methods: EMT6 tumours (mouse mammary carcinoma) were implanted into the subcutaneous tissue of both thighs of 10 BALB/c mice (one heated, one control tumour per animal). The target thermal dose was 41.5°C × 45 min. Without interrupting heating, 64Cu-ATSM (mean activity 1.8 mCi) was then injected and serial PET scans were obtained. In a sub-group of four animals, a low administered activity (∼0.3 mCi) 64Cu-ATSM scan was also conducted before heating to permit a direct comparison of the effects of hyperthermia on the same tumours. In another sub-group of five animals, a low activity (∼0.3 mCi) 64Cu-PTSM (pyruvaldehyde-bis(N*-methylthiosemicarbazone)) scan was conducted before heating, to confirm a posited correlation between perfusion and early 64Cu-ATSM uptake.Results: This study corrected for perfusion differences by dividing tumour uptake by the average early (first minute) uptake (‘self-normalized uptake’). The 10 heated tumours showed a significantly (p = 0.007) lower self-normalized uptake than control tumours by 2 min. For the four mice with low activity Cu-ATSM scans performed before hyperthermia, the tumours to be heated demonstrated self-normalized uptake consistent with the unheated control tumours and which departed significantly (p ≤ 0.02) from their post-hyperthermia scans by 5 min. Comparisons between scans and needle electrode surveys were performed in an additional four animals with eight tumours. For technical reasons electrode surveys were done after the end of hyperthermia—and, therefore, these animals also had comparison scans taken after hyperthermia. Reduced self-normalized uptake on scans was associated with increased pO2 on electrode surveys. These data also suggested a substantial degradation of the effect on tumour hypoxia by ∼15–45 min after the end of mild hyperthermia.Conclusion: Short imaging times of ∼5 min with modest (∼4–10) numbers of mice can discriminate the effects of mild hyperthermia on tumour physiology. The long-term objective is to use this tool to identify as short and mild a hyperthermia session as possible.
An accurate and noninvasive method for assessing treatment response following radiotherapy is needed for both treatment monitoring and planning. Measurement of solid tumor volume alone is not sufficient for reliable early detection of therapeutic response, since changes in physiological and/or biomechanical properties can precede tumor volume change following therapy. In this study, we use magnetic resonance elastography to evaluate the treatment effect after radiotherapy in a murine brain tumor model. Shear modulus was calculated and compared between the delineated tumor region of interest (ROI) and its contralateral, mirrored counterpart. We also compared the shear modulus from both the irradiated and non-irradiated tumor and mirror ROIs longitudinally, sampling four time points spanning 9–19 d post tumor implant. Results showed that the tumor ROI had a lower shear modulus than that of the mirror ROI, independent of radiation. The shear modulus of the tumor ROI decreased over time for both the treated and untreated groups. By contrast, the shear modulus of the mirror ROI appeared to be relatively constant for the treated group, while an increasing trend was observed for the untreated group. The results provide insights into the tumor properties after radiation treatment and demonstrate the potential of using the mechanical properties of the tumor as a biomarker. In future studies, more closely spaced time points will be employed for detailed analysis of the radiation effect.
520 Objectives To evaluate the ability of FDG and three 18F-labeled amino acids targeting different transport systems to distinguish mouse DBT gliomas from radiation necrosis using microPET. Methods Radiation necrosis was induced in the brains of BALB/c mice (n=4) with a single 60 Gy fraction using a gamma knife system. Approximately 6 weeks after irradiation, the mice underwent MRI for lesion confirmation followed by dynamic microPET using the 18F-labeled tracers (R)-MeFAMP (system A substrate), FET (system L substrate), (S)-AFETP (cationic amino acid transport substrate), and FDG. These tracers were also evaluated in a separate group of mice implanted with intracranial DBT gliomas (n=3 or 4). The percent change in SUV between early (7.5-12.5 min) and late (47.5-60 min) time points was compared using 2-tailed t-tests. Results For each tracer, the average SUVs were similar in the DBT tumors and radiation necrosis lesions, possibly due to the relatively short time interval between irradiation and imaging. The percentage of activity present at the late time point relative to the early time point was significantly different for radiation necrosis versus DBT tumors with FDG and MeFAMP but not with AFETP or FET. In the case of FDG, uptake was decreased at the late time point in radiation necrosis (83±11% of early value) but was increased at the late time point in the DBT tumors (131±30% of early value, p = 0.04). In the case of MeFAMP, uptake was also decreased at the late time point in radiation necrosis (44±4% of early value) but was relatively constant at the late time point in DBT tumors (94±17% of early value, p = 0.03). Conclusions The kinetics, but not the absolute amount of uptake, of FDG and MeFAMP appear to distinguish radiation necrosis from DBT tumors in this model. This relatively simple PET imaging paradigm could be adapted for evaluating patients with brain tumors after radiation therapy. Research Support NIH/NCI P50CA094056 (Washington University Molecular Imaging Center) K08CA15479
This feasibility study was undertaken to determine whether myocardial blood flow (MBF, mL/g/min) could be quantified noninvasively in small rodents using microPET and 15O-water or 1-11C-acetate.MBF was measured in 18 healthy rats using PET and 15O-water (MBF-W) under different interventions and compared with direct measurements obtained with microspheres (MBF-M). Subsequently, MBF was estimated in 24 rats at rest using 1-11C-acetate (MBF-Ace) and compared with measurements obtained with 15O-water. Using factor analysis, images were processed to obtain 1 blood and 1 myocardial time-activity curve per tracer per study. MBF-W was calculated using a well-validated 1-compartment kinetic model. MBF-Ace was estimated using a simple 1-compartment model to estimate net tracer uptake, K1 (K1 (mL/g/min) = MBF.E; E = first-pass myocardial extraction of 1-11C-acetate) and washout (k2 (min(-1))) along with F(BM) (spillover correction) after fixing F(MM) (partial-volume correction) to values obtained from 15O-water modeling. K1 values were converted to MBF values using a first-pass myocardial extraction/flow relationship measured in rats (E = 1.0-0.74.exp(-1.13/MBF)).In the first study, MBF-W correlated well with MBF-M (y = 0.74x + 0.96; n = 18, r = 0.91, P < 0.0001). However, the slope was different than unity, P < 0.05). Refitting of the data after forcing the intercept to be zero resulted in a nonbias correlation between MBF-W and MBF-M (y = 0.95x + 0.0; n = 18, r = 0.86, P < 0.0001) demonstrating that the underestimation of the slope could be attributed to the overestimation of MBF-W for 2 MBF-M values lower than 1.50 mL/g/min. In the second study, MBF-Ace values correlated well with MBF-W with no underestimation of MBF (y = 0.91x + 0.35; n = 24, r = 0.87, P < 0.0001).MBF can be quantified by PET using (15)O-water or 1-11C-acetate in healthy rats. Future studies are needed to determine the accuracy of the methods in low-flow states and to develop an approach for a partial-volume correction when 1-11C-acetate is used.
// Dinesh Thotala 1, 4 , Rowan M. Karvas 1 , John A. Engelbach 3 , Joel R. Garbow 2, 3, 4 , Andrew N. Hallahan 1 , Todd A. DeWees 1 , Andrei Laszlo 1 , Dennis E. Hallahan 1, 3, 4, 5 1 Department of Radiation Oncology, Washington University in St. Louis, Missouri, USA 2 School of Medicine, Washington University in St. Louis, Missouri, USA 3 Mallinckrodt Institute of Radiology, Washington University in St. Louis, Missouri, USA 4 Siteman Cancer Center, Washington University in St. Louis, Missouri, USA 5 Hope Center, Washington University in St. Louis, Missouri, USA Correspondence to: Dennis E. Hallahan, e-mail: dhallahan@radonc.wustl.edu Keywords: valproic acid (VPA), neuroprotection, histone deacetylase (HDAC), radioprotection, cancer therapy Received: May 29, 2014 Accepted: September 04, 2015 Published: September 16, 2015 ABSTRACT Neurocognitive deficits are serious sequelae that follow cranial irradiation used to treat patients with medulloblastoma and other brain neoplasms. Cranial irradiation causes apoptosis in the subgranular zone of the hippocampus leading to cognitive deficits. Valproic acid (VPA) treatment protected hippocampal neurons from radiation-induced damage in both cell culture and animal models. Radioprotection was observed in VPA-treated neuronal cells compared to cells treated with radiation alone. This protection is specific to normal neuronal cells and did not extend to cancer cells. In fact, VPA acted as a radiosensitizer in brain cancer cells. VPA treatment induced cell cycle arrest in cancer cells but not in normal neuronal cells. The level of anti-apoptotic protein Bcl-2 was increased and the pro-apoptotic protein Bax was reduced in VPA treated normal cells. VPA inhibited the activities of histone deacetylase (HDAC) and glycogen synthase kinase-3β (GSK3β), the latter of which is only inhibited in normal cells. The combination of VPA and radiation was most effective in inhibiting tumor growth in heterotopic brain tumor models. An intracranial orthotopic glioma tumor model was used to evaluate tumor growth by using dynamic contrast-enhanced magnetic resonance (DCE MRI) and mouse survival following treatment with VPA and radiation. VPA, in combination with radiation, significantly delayed tumor growth and improved mouse survival. Overall, VPA protects normal hippocampal neurons and not cancer cells from radiation-induced cytotoxicity both in vitro and in vivo . VPA treatment has the potential for attenuating neurocognitive deficits associated with cranial irradiation while enhancing the efficiency of glioma radiotherapy.
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