Dataset Information

Molecular imaging HDACs class IIa expression-activity and pharmacologic inhibition in intracerebral glioma models in rats using PET/CT/(MRI) with [18F]TFAHA.

ABSTRACT: HDAC class IIa enzymes (HDAC4, 5, 7, 9) are important for glioma progression, invasion, responses to TMZ and radiotherapy, and prognosis. In this study, we demonstrated the efficacy of PET/CT/(MRI) with [18F]TFAHA for non-invasive and quantitative imaging of HDAC class IIa expression-activity in intracerebral 9L and U87-MG gliomas in rats. Increased accumulation of [18F]TFAHA in 9L and U87-MG tumors was observed at 20 min post radiotracer administration with SUV of 1.45 ± 0.05 and 1.08 ± 0.05, respectively, and tumor-to-cortex SUV ratios of 1.74 ± 0.07 and 1.44 ± 0.03, respectively. [18F]TFAHA accumulation was also observed in normal brain structures known to overexpress HDACs class IIa: hippocampus, n.accumbens, PAG, and cerebellum. These results were confirmed by immunohistochemical staining of brain tissue sections revealing the upregulation of HDACs 4, 5, and 9, and HIF-1α, hypoacetylation of H2AK5ac, H2BK5ac, H3K9ac, H4K8ac, and downregulation of KLF4. Significant reduction in [18F]TFAHA accumulation in 9L tumors was observed after administration of HDACs class IIa specific inhibitor MC1568, but not the SIRT1 specific inhibitor EX-527. Thus, PET/CT/(MRI) with [18F]TFAHA can facilitate studies to elucidate the roles of HDAC class IIa enzymes in gliomagenesis and progression and to optimize therapeutic doses of novel HDACs class IIa inhibitors in gliomas.

SUBMITTER: Laws MT

PROVIDER: S-EPMC6401080 | biostudies-other | 2019 Mar

REPOSITORIES: biostudies-other

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Molecular imaging HDACs class IIa expression-activity and pharmacologic inhibition in intracerebral glioma models in rats using PET/CT/(MRI) with [18F]TFAHA.

Laws Maxwell T MT Bonomi Robin E RE Kamal Swatabdi S Gelovani David J DJ Llaniguez Jeremy J Potukutchi Shreya S Lu Xin X Mangner Thomas T Gelovani Juri G JG

Scientific reports 20190305 1

HDAC class IIa enzymes (HDAC4, 5, 7, 9) are important for glioma progression, invasion, responses to TMZ and radiotherapy, and prognosis. In this study, we demonstrated the efficacy of PET/CT/(MRI) with [18F]TFAHA for non-invasive and quantitative imaging of HDAC class IIa expression-activity in intracerebral 9L and U87-MG gliomas in rats. Increased accumulation of [18F]TFAHA in 9L and U87-MG tumors was observed at 20 min post radiotracer administration with SUV of 1.45 ± 0 ...[more]

PMID: 30837601

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Project description:PurposeConventional magnetic resonance imaging (MRI) can for glioma assessment be supplemented by positron emission tomography (PET) imaging with radiolabeled amino acids such as O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET), which provides additional information on metabolic properties. In neuro-oncology, patients often undergo brain and skull altering treatment, which is known to challenge MRI-based attenuation correction (MR-AC) methods and thereby impact the simplified semi-quantitative measures such as tumor-to-brain ratio (TBR) used in clinical routine. The aim of the present study was to examine the applicability of our deep learning method, DeepDixon, for MR-AC in [18F]FET PET/MRI scans of a post-surgery glioma cohort with metal implants.MethodsThe MR-AC maps were assessed for all 194 included post-surgery glioma patients (318 studies). The subgroup of 147 patients (222 studies, 200 MBq [18F]FET PET/MRI) with tracer uptake above 1 ml were subsequently reconstructed with DeepDixon, vendor-default atlas-based method, and a low-dose computed tomography (CT) used as reference. The biological tumor volume (BTV) was delineated on each patient by isocontouring tracer uptake above a TBR threshold of 1.6. We evaluated the MR-AC methods using the recommended clinical metrics BTV and mean and maximum TBR on a patient-by-patient basis against the reference with CT-AC.ResultsNinety-seven percent of the studies (310/318) did not have any major artifacts using DeepDixon, which resulted in a Dice coefficient of 0.89/0.83 for tissue/bone, respectively, compared to 0.84/0.57 when using atlas. The average difference between DeepDixon and CT-AC was within 0.2% across all clinical metrics, and no statistically significant difference was found. When using DeepDixon, only 3 out of 222 studies (1%) exceeded our acceptance criteria compared to 72 of the 222 studies (32%) with the atlas method.ConclusionWe evaluated the performance of a state-of-the-art MR-AC method on the largest post-surgical glioma patient cohort to date. We found that DeepDixon could overcome most of the issues arising from irregular anatomy and metal artifacts present in the cohort resulting in clinical metrics within acceptable limits of the reference CT-AC in almost all cases. This is a significant improvement over the vendor-provided atlas method and of particular importance in response assessment.

Project description:The purpose of this study was to compare the diagnostic performance of 18F-DCFBC PET/CT, a first-generation 18F-labeled prostate-specific membrane antigen (PSMA)-targeted agent, and 18F-NaF PET/CT, a sensitive marker of osteoblastic activity, in a prospective cohort of patients with metastatic prostate cancer. Methods: Twenty-eight prostate cancer patients with metastatic disease on conventional imaging prospectively received up to 4 PET/CT scans. All patients completed baseline 18F-DCFBC PET/CT and 18F-NaF PET/CT scans, and 23 patients completed follow-up imaging, with a median follow-up interval of 5.7 mo (range, 4.2-12.6 mo). Lesion detection was compared across the 2 PET/CT agents at each time point. Detection and SUV characteristics of each PET/CT agent were compared with serum prostate-specific antigen (PSA) levels and treatment status at the time of baseline imaging using nonparametric statistical testing (Spearman correlation, Wilcoxon rank). Results: Twenty-six patients had metastatic disease detected on 18F-NaF or 18F-DCFBC at baseline, and 2 patients were negative on both scans. Three patients demonstrated soft tissue-only disease. Of 241 lesions detected at baseline, 56 were soft-tissue lesions identified by 18F-DCFBC only and 185 bone lesions detected on 18F-NaF or 18F-DCFBC. 18F-NaF detected significantly more bone lesions than 18F-DCFBC (P < 0.001). Correlation of PSA with patient-level SUV metrics was strong in 18F-DCFBC (? > 0.5, P < 0.01) and poor in 18F-NaF (? < 0.3, P > 0.1). When PSA levels were combined with treatment status, patients with below-median levels of PSA (<2 ng/mL) on androgen deprivation therapy (n = 11) demonstrated more lesions on 18F-NaF than 18F-DCFBC (P = 0.02). In PSA greater than 2 ng/mL, patients on androgen deprivation therapy (n = 8) showed equal to or more lesions on 18F-DCFBC than on 18F-NaF. Conclusion: The utility of PSMA-targeting imaging in metastatic prostate cancer appears to depend on patient disease course and treatment status. Compared with 18F-NaF PET/CT, 18F-DCFBC PET/CT detected significantly fewer bone lesions in the setting of early or metastatic castrate-sensitive disease on treatment. However, in advanced metastatic castrate-resistant prostate cancer, 18F-DCFBC PET/CT shows good concordance with NaF PET/CT.

Dataset Information

Molecular imaging HDACs class IIa expression-activity and pharmacologic inhibition in intracerebral glioma models in rats using PET/CT/(MRI) with [18F]TFAHA.

Publications

Molecular imaging HDACs class IIa expression-activity and pharmacologic inhibition in intracerebral glioma models in rats using PET/CT/(MRI) with [<sup>18</sup>F]TFAHA.

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