scholarly journals 18F-Trifluoromethylated D-Cysteine as a Promising New PET Tracer for Glioma Imaging: Comparative Analysis With MRI and Histopathology in Orthotopic C6 Models

2021 ◽  
Vol 11 ◽  
Author(s):  
Hui Ma ◽  
Jing Zhao ◽  
Shaoyu Liu ◽  
Dingxiang Xie ◽  
Zhanwen Zhang ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Tumor Volume ◽  
C6 Glioma ◽  
C6 Glioma Cells ◽  
Normal Brain ◽  
Sprague Dawley ◽  
Dce Mri ◽  
Pet Tracer ◽  
Contrast Enhanced ◽  
Tracer Accumulation

Comparing MRI and histopathology, this study aims to comprehensively explore the potential application of 18F-trifluoromethylated D-cysteine (S-[18F]CF3-D-CYS) in evaluating glioma by using orthotopic C6 glioma models. Sprague–Dawley (SD) rats (n = 9) were implanted with C6 glioma cells. Tumor growth was monitored every week by multiparameter MRI [including dynamic contrast-enhanced MRI (DCE-MRI)], [18F]FDG, S-[18F]CF3-D-CYS, and [18F]FDOPA PET imaging. Repeated scans of the same rat with the two or three [18F]-labeled radiotracers were investigated. Initial regions of interest were manually delineated on T2WI and set on the same level of PET images, and tumor-to-normal brain uptake ratios (TNRs) were calculated to semiquantitatively assess the tracer accumulation in the tumor. The tumor volume in PET and histopathology was calculated. HE and Ki67 immunohistochemical staining were further performed. The correlations between the uptake of S-[18F]CF3-D-CYS and Ki67 were analyzed. Dynamic S-[18F]CF3-D-CYS PET imaging showed tumor uptake rapidly reached a peak, maintained plateau during 10–30 min after injection, then decreased slowly. Compared with [18F]FDG and [18F]FDOPA PET imaging, S-[18F]CF3-D-CYS PET demonstrated the highest TNRs (P < 0.05). There were no significant differences in the tumor volume measured on S-[18F]CF3-D-CYS PET or HE specimen. Furthermore, our results showed that the uptake of S-[18F]CF3-D-CYS was significantly positively correlated with tumor Ki67, and the poor accumulated S-[18F]CF3-D-CYS was consistent with tumor hemorrhage. There was no significant correlation between the S-[18F]CF3-D-CYS uptakes and the Ktrans values derived from DCE-MRI. In comparison with MRI and histopathology, S-[18F]CF3-D-CYS PET performs well in the diagnosis and evaluation of glioma. S-[18F]CF3-D-CYS PET may serve as a valuable tool in the clinical management of gliomas.

scholarly journals Radiosynthesis and Preliminary Biological Evaluation of 18F-Fluoropropionyl-Chlorotoxin as a Potential PET Tracer for Glioma Imaging

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Jing Zhao ◽  
Yu-liang Wang ◽  
Xin-bei Li ◽  
Si-yuan Gao ◽  
Shao-yu Liu ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Biological Evaluation ◽  
Brain Parenchyma ◽  
C6 Glioma ◽  
Small Animal Pet ◽  
Matrix Metalloproteinase 2 ◽  
Normal Brain ◽  
High Accumulation ◽  
Pet Tracer

Purposes. Chlorotoxin can specifically bind to matrix metalloproteinase 2 (MMP-2), which are overexpressed in the glioma. In this work, radiosynthesis of [18F]-fluoropropionyl-chlorotoxin ([18F]-FP-chlorotoxin) as a novel PET tracer was investigated, and biodistribution in vivo and PET imaging were performed in the C6 glioma model. Procedures. [18F]-FP-chlorotoxin was prepared from the reaction of chlorotoxin with [18F]-NFB (4-nitrophenyl 2-[18F]-fluoropropionate), which was synthesized from multistep reactions. Biodistribution was determined in 20 normal Kunming mice. Small-animal PET imaging with [18F]-FP-chlorotoxin was performed on the same rats bearing orthotopic C6 glioma at different time points (60 min, 90 min, and 120 min) after injection and compared with 2-deoxy-2-[18F] fluoro-D-glucose ([18F]-FDG). Results. [18F]-FP-Chlorotoxin was successfully synthesized in the radiochemical yield of 41% and the radiochemical purity of more than 98%. Among all the organs, the brain had the lowest and stable uptake of [18F]-FP-chlorotoxin, while the kidney showed the highest uptake. Compared with [18F]-FDG, a low uptake of [18F]-FP-chlorotoxin was detected in normal brain parenchyma and a high accumulation of [18F]-FP-chlorotoxin was found in the gliomas tissue. The glioma to normal brain uptake ratio of [18F]-FP-chlorotoxin was higher than that of [18F]-FDG. Furthermore, the uptake of [18F]-FP-chlorotoxin at 90 min after injection was better than that at 60 min after injection. Conclusions. Compared with [18F]-FDG, [18F]-FP-chlorotoxin has a low and stable uptake in normal brain parenchyma. [18F]-FP-Chlorotoxin seems to be a potential PET tracer with a good performance in diagnosis of the glioma.

Dynamic contrast-enhanced magnetic resonance imaging for monitoring the anti-angiogenesis efficacy in a C6 glioma rat model

2019 ◽  
Vol 61 (7) ◽  
pp. 973-982 ◽  
Author(s):  
Weishu Hou ◽  
Xiaohu Li ◽  
Hongli Pan ◽  
Man Xu ◽  
Sixing Bi ◽  
...  
Keyword(s):  
Tumor Volume ◽  
Treated Group ◽  
C6 Glioma ◽  
Control Group ◽  
Resonance Imaging ◽  
Dce Mri ◽  
Angiogenic Therapy ◽  
Dynamic Contrast Enhanced ◽  
Contrast Enhanced ◽  
Early Effects

Background Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is useful in predicting responses to angiogenic therapy of malignant tumors. Purpose To observe the dynamics of DCE-MRI parameters in evaluating early effects of antiangiogenic therapy in a C6 glioma rat model. Material and Methods The Bevacizumab or vehicle treatment was started from the 14th day after glioma model was established. The treated and control groups (n = 13 per group) underwent DCE-MRI scans on days 0, 1, 3, 5, and 7 after treatment. Tumor volume was calculated according to T2-weighted images. Hematoxylin and eosin, microvessel density (MVD), and proliferating cell nuclear antigen (PCNA) examination were performed on day 7. The MRI parameters between the two groups were compared and correlations with immunohistochemical scores were analyzed. Results The average tumor volume of treated group was significantly lower than that of control group on day 7 (81.764 ± 1.043 vs. 103.634 ± 3.868 mm3, P =  0.002). Ktrans and Kep decreased in the treated group while they increased in the control group. The differences were observed on day 5 (Ktrans: 0.045 ± 0.018 vs. 0.093 ± 0.014 min−1, P <  0.001; Kep: 0.062 ± 0.018 vs. 0.134 ± 0.047 min−1, P =  0.005) and day 7 (Ktrans: 0.032 ± 0.010 vs. 0.115 ± 0.025 min−1, P <  0.001; Kep: 0.045 ± 0.016 vs. 0.144 ± 0.042 min−1, P <  0.001). The difference of Ve was observed on day 5 (0.847 ± 0.248 vs. 0.397 ± 0.151, P =  0.009) and 7 (0.920 ± 0.154 vs. 0.364 ± 0.105, P =  0.006). Ktrans and Kep showed positive correlations with MVD and Ve showed negative correlation with PCNA. Conclusion DCE-MRI can assess the changes of early effects of anti-angiogenic therapy in preclinical practice.

Evaluation of neovascularization patterns in an orthotopic rat glioma model with dynamic contrast-enhanced MRI

2016 ◽  
Vol 58 (9) ◽  
pp. 1138-1146 ◽  
Author(s):  
Du Xuesong ◽  
Xue Wei ◽  
Liu Heng ◽  
Chen Xiao ◽  
Wang Shunan ◽  
...  
Keyword(s):  
Imaging Biomarker ◽  
Sprague Dawley ◽  
Post Transplantation ◽  
Dce Mri ◽  
Time Points ◽  
Dynamic Contrast Enhanced ◽  
Contrast Enhanced ◽  
Intussusceptive Microvascular Growth ◽  
Glioma Model ◽  
Vascular Mimicry

Background Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been proved useful in evaluating glioma angiogenesis, but the utility in evaluating neovascularization patterns has not been reported. Purpose To evaluate in vivo real-time glioma neovascularization patterns by measuring glioma perfusion quantitatively using DCE-MRI. Material and Methods Thirty Sprague-Dawley rats were used to establish C6 orthotopic glioma model and underwent MRI and pathology detections. As MRI and pathology were performed at six time points (i.e. 4, 8, 12, 16, 20, and 24 days) post transplantation, neovascularization patterns were evaluated via DCE-MRI. Results Four neovascularization patterns were observed in glioma tissues. Sprout angiogenesis and intussusceptive microvascular growth located inside tumor, while vascular co-option and vascular mimicry were found in the tumor margin and necrotic area, respectively. Sprout angiogenesis and intussusceptive microvascular growth increased with Ktrans, Kep, and Vp inside tumor tissue. In addition, Kep and Vp were positively correlated with sprout angiogenesis and intussusceptive microvascular growth. Vascular co-option was decreased at 12 and 16 days post transplantation and correlated negatively with Ktrans and Kep detected in the glioma margin, respectively. Changes of vascular mimicry showed no significant statistical difference at the six time points. Conclusion Our results indicate that DCE-MRI can evaluate neovascularization patterns in a glioma model. Furthermore, DCE-MRI could be an imaging biomarker for guidance of antiangiogenic treatments in humans in the future.

scholarly journals Maximizing the use of batch production of 18F-FDOPA for imaging of brain tumors to increase availability of hybrid PET/MR imaging in clinical setting

2020 ◽  
Author(s):  
M S Aboian ◽  
R Barajas ◽  
J Shatalov ◽  
V Ravanfar ◽  
E Bahroos ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Amino Acid ◽  
Brain Tumors ◽  
Pet Imaging ◽  
Critical Role ◽  
Normal Brain ◽  
Mri Imaging ◽  
Pet Tracer ◽  
Amino Acid Pet ◽  
The Cost

Abstract Background Amino acid PET imaging of brain tumors has been shown to play an important role in predicting tumor grade, delineation of tumor margins, and differentiating tumor recurrence from the background of post-radiation changes, but is not commonly used in clinical practice due to high cost. We propose that PET/MRI imaging of patients grouped to the day of tracer radiosynthesis will significantly decrease the cost of PET imaging, which will improve patient access to PET. Methods Seventeen patients with either primary brain tumors or metastatic brain tumors were recruited for imaging on 3T PET/MRI and were scanned on 4 separate days in groups of 3-5 patients. The first group of consecutively imaged patients contained three patients, followed by two groups of 5 patients, and last group of 4 patients. Results For each of the patients, standard of care gadolinium enhanced MRI and dynamic PET imaging with 18F-FDOPA amino acid tracer was obtained. The total cost savings of scanning 17 patients in batches of 4 as opposed to individual radiosynthesis was 48.5% ($28,321). Semiquantitative analysis of tracer uptake in normal brain were performed with appropriate accumulation and expected subsequent washout. Conclusion Amino acid PET tracers have been shown to play a critical role in characterization of brain tumors but their adaptation to clinical practice has been limited due to high cost of PET. Scheduling patient imaging to maximally utilize the radiosynthesis of imaging tracer significantly reduces the cost of PET and results in increased availability of PET tracer use in neuro-oncology.

Trans sodium crocetinate: functional neuroimaging studies in a hypoxic brain tumor

2011 ◽  
Vol 115 (4) ◽  
pp. 749-753 ◽  
Author(s):  
Jason P. Sheehan ◽  
Britney Popp ◽  
Stephen Monteith ◽  
Sushila Toulmin ◽  
Jennifer Tomlinson ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Functional Neuroimaging ◽  
Positron Emission Tomography Imaging ◽  
Immunoblot Analysis ◽  
Saline Group ◽  
C6 Glioma Cells ◽  
Normal Brain ◽  
The Mean ◽  
Relative Uptake

Object Intratumoral hypoxia is believed to be exhibited in high-grade gliomas. Trans sodium crocetinate (TSC) has been shown to increase oxygen diffusion to hypoxic tissues. In this research, the authors use oxygen-sensitive PET studies to evaluate the extent of hypoxia in vivo in a glioblastoma model and the effect of TSC on the baseline oxygenation of the tumor. Methods The C6 glioma cells were stereotactically implanted in the right frontal region of rat brains. Formation of intracranial tumors was confirmed on MR imaging. Animals were injected with Copper(II) diacetyl-di(N4-methylthiosemicarbazone) (Cu-ATSM) and then either TSC or saline (6 rats each). Positron emission tomography imaging was performed, and relative uptake values were computed to determine oxygenation within the tumor and normal brain parenchyma. Additionally, TSC or saline was infused into the animals, and carbonic anhydrase 9 (CA9) and hypoxia-inducing factor–1α (HIF-1α) protein expression were measured 1 day afterward. Results On PET imaging, all glioblastoma tumors demonstrated a statistically significant decrease in uptake of Cu-ATSM compared with the contralateral cerebral hemisphere (p = 0.000002). The mean relative uptake value of the tumor was 3900 (range 2203–6836), and that of the contralateral brain tissue was 1017 (range 488–2304). The mean relative hypoxic tumor volume for the saline group and TSC group (6 rats each) was 1.01 ± 0.063 and 0.69 ± 0.062, respectively (mean ± SEM, p = 0.002). Infusion of TSC resulted in a 31% decrease in hypoxic volume. Immunoblot analysis revealed expression of HIF-1α and CA9 in all tumor specimens. Conclusions Some glioblastomas exhibit hypoxia that is demonstrable on oxygen-specific PET imaging. It appears that TSC lessens intratumoral hypoxia on functional imaging. Further studies should explore relative hypoxia in glioblastoma and the potential therapeutic gains that can be achieved by lessening hypoxia during delivery of adjuvant treatment.

scholarly journals Characterization of Tumor Angiogenesis in Rat Brain Using Iron-Based Vessel Size Index MRI in Combination with Gadolinium-Based Dynamic Contrast-Enhanced MRI

2009 ◽  
Vol 29 (10) ◽  
pp. 1714-1726 ◽  
Author(s):  
Marine Beaumont ◽  
Benjamin Lemasson ◽  
Régine Farion ◽  
Christoph Segebarth ◽  
Chantal Rémy ◽  
...  
Keyword(s):  
Time Frame ◽  
C6 Glioma ◽  
Vessel Size ◽  
Dce Mri ◽  
Dynamic Contrast Enhanced Mri ◽  
Dynamic Contrast Enhanced ◽  
Contrast Enhanced ◽  
Size Index ◽  
Iron Based ◽  
Contrast Enhanced Mri

This study aimed at combining an iron-based, steady-state, vessel size index magnetic resonance imaging (VSI MRI) approach, and a gadolinium (Gd)-based, dynamic contrast-enhanced MRI approach (DCE MRI) to characterize tumoral microvasculature. Rats bearing an orthotopic glioma (C6, n=14 and RG2, n=6) underwent DCE MRI and combined VSI and DCE MRI 4 h later, at 2.35 T. Gd-DOTA (200 μmol of Gd per kg) and ultrasmall superparamagnetic iron oxide (USPIO) (200 μmol of iron per kg) were used for DCE and VSI MRI, respectively. C6 and RG2 gliomas were equally permeable to Gd-DOTA but presented different blood volume fractions and VSI, in good agreement with histologic data. The presence of USPIO yielded reduced Ktrans values. The Ktrans values obtained with Gd-DOTA in the absence and in the presence of USPIO were well correlated for the C6 glioma but not for the RG2 glioma. It was also observed that, within the time frame of DCE MRI, USPIO remained intravascular in the C6 glioma whereas it extravasated in the RG2 glioma. In conclusion, VSI and DCE MRI can be combined provided that USPIO does not extravasate with the time frame of the DCE MRI experiment. The mechanisms at the origin of USPIO extravasation remain to be elucidated.

scholarly journals CBMT-03. EVALUATION OF PET TRACERS TO DIFFERENTIATE IDH1 MUTANT GBM

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi33-vi33
Author(s):  
Andrei Molotkov ◽  
Angeliki Mela ◽  
Peter D Canoll ◽  
Akiva Mintz
Keyword(s):  
Amino Acid ◽  
Pet Imaging ◽  
Causal Link ◽  
Amino Acid Derivative ◽  
Normal Brain ◽  
Pet Tracers ◽  
Pet Tracer ◽  
Altered Glucose ◽  
Pet Ct ◽  
18F Fdg

Abstract OBJECTIVE PET/CT offers the unique potential to noninvasively evaluate biomarker expression and aberrant metabolism. 18F-FDG has driven PET/CT to the forefront of cancer imaging, as altered glucose metabolism is a hallmark of oncogenesis. However, 18F-FDG is suboptimal for GBM due to high physiologic uptake in normal brain. The development of alternative tracers has reignited the field of PET/CT in GBM and offers hope for diagnosis and molecular staging in GBM. We hypothesize that fundamental differences in metabolism and oncogene expression present in IDH1 mutatant gliomas can be shown using PET imaging, as has been suggested in some correlative clinical studies. Our objective was therefore to establish a causal link between IDH1 mutation in GBM and uptake of targeted PET tracers in a unique proneural GBM transgenic model characterized by p53, IDH1 mutations and PDGF expression. METHODS We examined the uptake of 3 blood-brain-barrier (BBB) penetrant tracers that have been used in GBM: (a) 18F-FDG, a surrogate for increased glycolysis; (b) 18F-Fluciclovine, an amino acid derivative transported into cells through the energy-independent L-type amino acid transporter (LAT) system and is approved by the FDA for prostate cancer; and (c) 11C-ER176, a tracer that binds the TSPO receptor that is generally expressed on activated microglia as well as GBM. RESULTS We did not observe significant differences in 18F-FDG uptake between wt and IDH mutant GBM cells. However, we found that IDH mutant GBM cells demonstrated significantly increased 18F-Fluciclovine (47%) and 11C-ER176 (53%) versus IDH wt cells. CONCLUSION We have established a causal link between IDH mutation status and uptake of (a) 18F-Fluciclovine, a promising FDA approved PET tracer and (b) 11C-ER176, a second generation TSPO ligand. Thus, we are performing further studies in orthotopic syngeneic GBM models to determine if PET imaging can non-invasively demonstrate molecular characterization and therapeutic stratification in glioma.

scholarly journals NIMG-04. MRI EVALUATION OF THE EFFECT OF WHOLE BRAIN RADIOTHERAPY ON BRAIN METASTASIS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii147-ii147
Author(s):  
William Crowe ◽  
Dawen Zhao ◽  
Zhongwei Zhang ◽  
Lulu Wang ◽  
John Bourland
Keyword(s):  
Brain Metastasis ◽  
Cytotoxic Effect ◽  
Tumor Volume ◽  
Whole Brain Radiotherapy ◽  
Whole Brain ◽  
Dce Mri ◽  
Brain Radiotherapy ◽  
Contrast Enhanced ◽  
Longitudinal Mri ◽  
Bbb Permeability

Abstract Poor prognosis of breast cancer brain metastasis partially results from the inability of therapeutics to penetrate the Blood-Brain-Barrier (BBB). Whole Brain Radiotherapy (WBRT) is standard-of-care for brain metastasis, however the early effects of fractionated WBRT on brain metastases have not been evaluated. Here, we applied longitudinal MRI to study WBRT’s effect on tumor volume, BBB permeability, and tumor-cell killing using anatomic, Dynamic Contrast Enhanced (DCE), and Diffusion-weighted (DW) MRI, evaluating tumor volume, permeability, and cytotoxic effect, respectively. The BCBM mouse model was established with left ventricle MDA-MB231-Br cell injection. MRI occurred before and 24h after 3 daily fractionated 4Gy WBRT (2.4Gy/min) or sham irradiation. In addition to anatomic MRI, DW MRI measured tissue ADC to study cytotoxic effect, and DCE MRI measured BBB permeability, quantified as the permeability variable Ktrans. Before treatment, T2-weighted images revealed hyperintense multifocal lesions in brains, and many had intact BBB indicated by no T1-w contrast-enhancement. WBRT tumors were smaller than sham irradiated tumors after 3 days (p&lt; 0.05), while no difference in the number of new lesions was observed. DW MRI demonstrated increased ADC in WBRT tumors (p&lt; 0.05), correlating well with elevated Caspase-3 staining of apoptotic cells. T1-w contrast enhanced images of tumors after treatment revealed no differences in the population of contrast-enhanced tumors between the WBRT and sham radiation groups. However, quantitative DCE MRI showed higher Ktrans in WBRT treated tumors relative to sham treated lesions, and an increase in Ktrans of WBRT tumors (p&lt; 0.05), despite high permeability heterogeneity both inter- and intra-tumorally, indicating remaining impermeable BBB. In addition to monitoring tumor volume, longitudinal MRI provided non-invasive assessments of temporal and spatial changes in cellularity and vascular permeability of brain metastasis in response to WBRT, which may prove to be useful for defining an ideal treatment window for potential combination BCBM treatments.

Radiosensitivity of glioma to Gamma Knife treatment enhanced in vitro and in vivo by RNA interfering Ku70 that is mediated by a recombinant adenovirus

2010 ◽  
Vol 113 (Special_Supplement) ◽  
pp. 228-235 ◽  
Author(s):  
Qiang Jia ◽  
Yanhe Li ◽  
Desheng Xu ◽  
Zhenjiang Li ◽  
Zhiyuan Zhang ◽  
...  
Keyword(s):  
Western Blot ◽  
Gamma Knife ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Glioma Cells ◽  
C6 Glioma ◽  
C6 Glioma Cells ◽  
C6 Cells

Object The authors sought to evaluate modification of the radiation response of C6 glioma cells in vitro and in vivo by inhibiting the expression of Ku70. To do so they investigated the effect of gene transfer involving a recombinant replication-defective adenovirus containing Ku70 short hairpin RNA (Ad-Ku70shRNA) combined with Gamma Knife treatment (GKT). Methods First, Ad-Ku70shRNA was transfected into C6 glioma cells and the expression of Ku70 was measured using Western blot analysis. In vitro, phenotypical changes in C6 cells, including proliferation, cell cycle modification, invasion ability, and apoptosis were evaluated using the MTT (3′(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide) assay, Western blot analysis, and cell flow cytometry. In vivo, parental C6 cells transfected with Ad-Ku70shRNA were implanted stereotactically into the right caudate nucleus in Sprague-Dawley rats. After GKS, apoptosis was analyzed using the TUNEL (terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling) method. The inhibitory effects on growth and invasion that were induced by expression of proliferating cell nuclear antigen and matrix metalloproteinase–9 were determined using immunohistochemical analyses. Results The expression of Ku70 was clearly inhibited in C6 cells after transfection with Ad-Ku70shRNA. In vitro following transfection, the C6 cells showed improved responses to GKT, including suppression of proliferation and invasion as well as an increased apoptosis index. In vivo following transfection of Ad-Ku70shRNA, the therapeutic efficacy of GKT in rats with C6 gliomas was greatly enhanced and survival times in these animals were prolonged. Conclusions Our data support the potential for downregulation of Ku70 expression in enhancing the radiosensitivity of gliomas. The findings of our study indicate that targeted gene therapy–mediated inactivation of Ku70 may represent a promising strategy in improving the radioresponsiveness of gliomas to GKT.

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