Koji Sagiyama

Amide proton transfer imaging of adult diffuse gliomas: correlation with histopathological grades.

BACKGROUND Amide proton transfer (APT) imaging is a novel molecular MRI technique to detect endogenous mobile proteins and peptides through chemical exchange saturation transfer. We prospectively assessed the usefulness of APT imaging in predicting the histological grade of adult diffuse gliomas. METHODS Thirty-six consecutive patients with histopathologically proven diffuse glioma (48.1 ± 14.7 y old, 16 males and 20 females) were included in the study. APT MRI was conducted on a 3T clinical scanner and was obtained with 2 s saturation at 25 saturation frequency offsets ω = -6 to +6 ppm (step 0.5 ppm). δB0 maps were acquired separately for a point-by-point δB0 correction. APT signal intensity (SI) was defined as magnetization transfer asymmetry at 3.5 ppm: magnetization transfer ratio (MTR)asym = (S[-3.5 ppm] - S[+3.5 ppm])/S0. Regions of interest were carefully placed by 2 neuroradiologists in solid parts within brain tumors. The APT SI was compared with World Health Organization grade, Ki-67 labeling index (LI), and cell density. RESULTS The mean APT SI values were 2.1 ± 0.4% in grade II gliomas (n = 8), 3.2 ± 0.9% in grade III gliomas (n = 10), and 4.1 ± 1.0% in grade IV gliomas (n = 18). Significant differences in APT intensity were observed between grades II and III (P < .05) and grades III and IV (P < .05), as well as between grades II and IV (P < .001). There were positive correlations between APT SI and Ki-67 LI (P = .01, R = 0.43) and between APT SI and cell density (P < .05, R = 0.38). The gliomas with microscopic necrosis showed higher APT SI than those without necrosis (P < .001). CONCLUSIONS APT imaging can predict the histopathological grades of adult diffuse gliomas.

In vivo chemical exchange saturation transfer imaging allows early detection of a therapeutic response in glioblastoma

Significance The prognosis and management of patients with glioma is vastly different depending on whether one detects tumor progression or treatment effects. Although the gold standard in the evaluation of treatment efficacy involves MRI, the currently available imaging methods often do not suffice to make the final decision. Our study demonstrated that amide proton transfer (APT) imaging, one subset of chemical exchange saturation transfer imaging, can detect molecular signals in glioma induced by short-term chemotherapy with temozolomide. These molecular events precede morphologic changes. The APT signal did not decrease in tumors resistant to chemotherapy. APT imaging may provide a useful prognostic biomarker of treatment response or tumor progression in glioma. Glioblastoma multiforme (GBM), which account for more than 50% of all gliomas, is among the deadliest of all human cancers. Given the dismal prognosis of GBM, it would be advantageous to identify early biomarkers of a response to therapy to avoid continuing ineffective treatments and to initiate other therapeutic strategies. The present in vivo longitudinal study in an orthotopic mouse model demonstrates quantitative assessment of early treatment response during short-term chemotherapy with temozolomide (TMZ) by amide proton transfer (APT) imaging. In a GBM line, only one course of TMZ (3 d exposure and 4 d rest) at a dose of 80 mg/kg resulted in substantial reduction in APT signal compared with untreated control animals, in which the APT signal continued to increase. Although there were no detectable differences in tumor volume, cell density, or apoptosis rate between groups, levels of Ki67 (index of cell proliferation) were substantially reduced in treated tumors. In another TMZ-resistant GBM line, the APT signal and levels of Ki67 increased despite the same course of TMZ treatment. As metabolite changes are known to occur early in the time course of chemotherapy and precede morphologic changes, these results suggest that the APT signal in glioma may be a useful functional biomarker of treatment response or degree of tumor progression. Thus, APT imaging may serve as a sensitive biomarker of early treatment response and could potentially replace invasive biopsies to provide a definitive diagnosis. This would have a major impact on the clinical management of patients with glioma.

Multi-chromatic pH-activatable 19F-MRI nanoprobes with binary ON/OFF pH transitions and chemical-shift barcodes

Magnetic resonance imaging (MRI) is a powerful noninvasive imaging technique that has greatly impacted basic biological research as well clinical diagnosis of cancer and other diseases.[1] Conventional MR contrast agents are T1 (e.g. Gd-DTPA) or T2-based (e.g. iron oxide), which cause significant longitudinal or transverse relaxation of protons, respectively.[2] Despite their success in many biological applications, one potential limitation is the lack of multi-chromatic features that allows for simultaneous detection of multiple signals. Recently, 19F has received significant attention in MR imaging and spectroscopy studies.[3] Compared to 1H-MRI, 19F-MRI has little biological background due to the low levels of endogenous fluorine in the body. Moreover, 19F has 100% natural abundance and its gyromagnetic ratio (40.06 MHz/T) is second only to 1H, which makes it more sensitive for detection over other nuclei.[3f]

Characterization of Lung Cancer by Amide Proton Transfer (APT) Imaging: An In-Vivo Study in an Orthotopic Mouse Model

Amide proton transfer (APT) imaging is one of the chemical exchange saturation transfer (CEST) imaging methods which images the exchange between protons of free tissue water and the amide groups (−NH) of endogenous mobile proteins and peptides. Previous work suggested the ability of APT imaging for characterization of the tumoral grade in the brain tumor. In this study, we tested the feasibility of in-vivo APT imaging of lung tumor and investigated whether the method could differentiate the tumoral types on orthotopic tumor xenografts from two malignant lung cancer cell lines. The results revealed that APT imaging is feasible to quantify lung tumors in the moving lung. The measured APT effect was higher in the tumor which exhibited more active proliferation than the other. The present study demonstrates that APT imaging has the potential to provide a characterization test to differentiate types or grade of lung cancer noninvasively, which may eventually reduce the need invasive needle biopsy or resection for lung cancer.

Scan-rescan reproducibility of parallel transmission based amide proton transfer imaging of brain tumors

To evaluate the reproducibility of amide proton transfer (APT) imaging of brain tumors using a parallel transmission‐based technique.

Molecular Platform for Design and Synthesis of Targeted Dual-Modality Imaging Probes

We report a versatile dendritic structure based platform for construction of targeted dual-modality imaging probes. The platform contains multiple copies of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) branching out from a 1,4,7-triazacyclononane-N,N′,N″-triacetic acid (NOTA) core. The specific coordination chemistries of the NOTA and DOTA moieties offer specific loading of 68/67Ga3+ and Gd3+, respectively, into a common molecular scaffold. The platform also contains three amino groups which can potentiate targeted dual-modality imaging of PET/MRI or SPECT/MRI (PET: positron emission tomography; SPECT: single photon emission computed tomography; MRI: magnetic resonance imaging) when further functionalized by targeting vectors of interest. To validate this design concept, a bimetallic complex was synthesized with six peripheral Gd-DOTA units and one Ga-NOTA core at the center, whose ion T1 relaxivity per gadolinium atom was measured to be 15.99 mM–1 s–1 at 20 MHz. Further, the bimetallic agent demonstrated its anticipated in vivo stability, tissue distribution, and pharmacokinetic profile when labeled with 67Ga. When conjugated with a model targeting peptide sequence, the trivalent construct was able to visualize tumors in a mouse xenograft model by both PET and MRI via a single dose injection.

Amide Proton Transfer Imaging of Diffuse Gliomas: Effect of Saturation Pulse Length in Parallel Transmission-Based Technique

In this study, we evaluated the dependence of saturation pulse length on APT imaging of diffuse gliomas using a parallel transmission-based technique. Twenty-two patients with diffuse gliomas (9 low-grade gliomas, LGGs, and 13 high-grade gliomas, HGGs) were included in the study. APT imaging was conducted at 3T with a 2-channel parallel transmission scheme using three different saturation pulse lengths (0.5 s, 1.0 s, 2.0 s). The 2D fast spin-echo sequence was used for imaging. Z-spectrum was obtained at 25 frequency offsets from -6 to +6 ppm (step 0.5 ppm). A point-by-point B0 correction was performed with a B0 map. Magnetization transfer ratio (MTRasym) and ΔMTRasym (contrast between tumor and normal white matter) at 3.5 ppm were compared among different saturation lengths. A significant increase in MTRasym (3.5 ppm) of HGG was found when the length of saturation pulse became longer (3.09 ± 0.54% at 0.5 s, 3.83 ± 0.67% at 1 s, 4.12 ± 0.97% at 2 s), but MTRasym (3.5 ppm) was not different among the saturation lengths in LGG. ΔMTRasym (3.5 ppm) increased with the length of saturation pulse in both LGG (0.48 ± 0.56% at 0.5 s, 1.28 ± 0.56% at 1 s, 1.88 ± 0.56% at 2 s and HGG (1.72 ± 0.54% at 0.5 s, 2.90 ± 0.49% at 1 s, 3.83 ± 0.88% at 2 s). In both LGG and HGG, APT-weighted contrast was enhanced with the use of longer saturation pulses.

Accelerated territorial arterial spin labeling based on shared rotating control acquisition: an observer study for validation

IntroductionShared rotating control acquisition can shorten the imaging time of territorial arterial spin labeling (tASL) by 33% compared with the normal control acquisition scheme but potentially results in an inaccurate estimate of vascular territories due to imperfect magnetization transfer compensation. Our purpose was to validate the accuracy of the shared rotating control acquisition method in evaluation of vascular territories.MethodsTwenty-four patients underwent tASL at a 3.0-T MRI with the conventional normal control acquisition method. Composite vascular territory maps, in which the blood flows from the right and left internal carotid arteries and the posterior circulation were encoded in red–green–blue, were generated as a normal averaged control-label scheme and as a simulated shared rotating control scheme. Two observers independently reported the most dominant territorial flow in 26 brain regions corresponding to the arterial segments at three post-labeling time points. Inter-reader and inter-method agreements were analyzed using κ statistics.ResultsOverall inter-reader agreements were excellent for both the normal control and the shared rotating control methods (κ = 0.98, respectively). Overall inter-method agreement was also excellent (κ = 0.98), although relatively low agreement was noted in the bilateral posterior cerebral artery territories (κ = 0.79 to 0.93).ConclusionOur results suggested that tASL using shared rotating control acquisition can provide information on the vascular territories comparable to that obtained using the normal control acquisition while substantially shortening the imaging time.

One-stop shop assessment for atrial septal defect closure using 256-slice coronary CT angiography.

ObjectivesTo investigate the feasibility and accuracy of measurement of the pulmonary to systemic blood flow ratio (Qp/Qs) and defect and rim sizes in secundum atrial septal defects (ASDs) using 256-slice CT, compared to the reference transoesophageal echocardiography (TEE) and right heart catheterization (RHC) measurements.MethodsTwenty-three consecutive adult patients with secundum ASDs who underwent retrospective ECG-gated coronary CT angiography (CCTA), TEE and RHC were enrolled in this study. Right ventricular (RV) and left ventricular (LV) stroke volumes (SV) were calculated by biventricular volumetry of CCTA. Qp/Qs-CT was defined as RVSV/LVSV. The sizes of the defect and rim were measured by multi-planar reconstruction CT images. Correlations between Qp/Qs-CT and Qp/Qs–RHC and between the defect diameter obtained by CT and TEE were analyzed by Pearson’s coefficient analysis. Rim sizes by CT and TEE were compared by paired t-test.ResultsQp/Qs-CT was significantly correlated with Qp/Qs-RHC (r = 0.83, p < 0.0001), and the defect diameter by CT was significantly correlated with that by TEE (r = 0.95, p < 0.0001). There was no significant difference between CT and TEE in measurements of rim size.Conclusions256-slice CCTA allows measuring Qp/Qs and size of defects and rims in patients with secundum ASDs, accomplishing pretreatment evaluation non-invasively and comprehensively.Key Points• Quantification of left-to-right shunting can be performed reliably and accurately by CT.• The sizes of defects and rims can be measured accurately using 256-slice CT.• 256-slice CT permits pretreatment evaluation of ASD non-invasively and comprehensively.

Multiparametric voxel-based analyses of standardized uptake values and apparent diffusion coefficients of soft-tissue tumours with a positron emission tomography/magnetic resonance system: Preliminary results

AbstractObjectivesTo investigate the usefulness of voxel-based analysis of standardized uptake values (SUVs) and apparent diffusion coefficients (ADCs) for evaluating soft-tissue tumour malignancy with a PET/MR system.MethodsThirty-five subjects with either ten low/intermediate-grade tumours or 25 high-grade tumours were prospectively enrolled. Zoomed diffusion-weighted and fluorodeoxyglucose (18FDG)-PET images were acquired along with fat-suppressed T2-weighted images (FST2WIs). Regions of interest (ROIs) were drawn on FST2WIs including the tumour in all slices. ROIs were pasted onto PET and ADC-maps to measure SUVs and ADCs within tumour ROIs. Tumour volume, SUVmax, ADCminimum, the heterogeneity and the correlation coefficients of SUV and ADC were recorded. The parameters of high- and low/intermediate-grade groups were compared, and receiver operating characteristic (ROC) analysis was also performed.ResultsThe mean correlation coefficient for SUV and ADC in high-grade sarcomas was lower than that of low/intermediate-grade tumours (−0.41 ± 0.25 vs. −0.08 ± 0.34, P < 0.01). Other parameters did not differ significantly. ROC analysis demonstrated that correlation coefficient showed the best diagnostic performance for differentiating the two groups (AUC 0.79, sensitivity 96.0%, specificity 60%, accuracy 85.7%).ConclusionsSUV and ADC determined via PET/MR may be useful for differentiating between high-grade and low/intermediate-grade soft tissue tumours.Key Points• PET/MR allows voxel-based comparison of SUVs and ADCs in soft-tissue tumours. • A comprehensive assessment of internal heterogeneity was performed with scatter plots. • SUVmax or ADCminimum could not differentiate high-grade sarcoma from low/intermediate-grade tumours. • Only the correlation coefficient between SUV and ADC differentiated the two groups. • The correlation coefficient showed the best diagnostic performance by ROC analysis.