FAP-Specific Signalling Is an Independent Diagnostic Approach in ACC and Not a Surrogate Marker of MRI Sequences.

BACKGROUND: Fibroblast Activation Protein (FAP) is a new target for positron emission tomography and computed tomography (PET/CT) imaging of epithelial tumours embedded in a fibrous stroma. Adenoid cystic carcinomas (ACCs) have shown elevated tracer uptake in 68Gallium (68Ga)-labelled FAPIs in previous studies. The current gold standard for ACC imaging is contrast-enhanced (ce) MRI, where intertumoural heterogeneity leads to variable appearance on T1-weighted (T1w) and T2-weighted (T2w) images. In this retrospective analysis, we correlated 68Ga-FAPI PET signalling at three time points with ceT1w and T2w MRI signals to further characterise the significance of 68Ga-FAPI uptake in ACCs. METHODS: Clinical PET/CT scans of 12 ACC patients were performed at 10, 60 and 180 min post i.v. administration of 68Ga-labelled-FAPI tracer molecules. 68Ga-PET- and corresponding MRI-scans were co-registered, and 3D volumetric segmentations were performed on ceT1w and T2w lesions of co-registered MRI slides. Signal intensity values of 68Ga-FAPI PET signalling and ceT1w/T2w MRI scans were analysed for their pixelwise correlation in each patient. Pooled estimates of the correlation coefficients were calculated using the Fisher z-transformation. RESULTS: 68Ga-FAPI PET signals showed a very weak positive correlation with ceT1w values (pooled correlation 0.114, 0.147 and 0.162 at 10, 60 and 180 min) and a weak negative correlation with T2w values (pooled correlation -0.148, -0.121 and -0.225 at 10, 60 and 180 min). Individual r-values at 60 min ranged from -0.130 to 0.434 in ceT1w and from -0.466 to 0.637 in T2w MRI scans. CONCLUSION: There are only slight correlations between the intensity of 68Ga-FAPI PET signals and tumour appearance in ceT1w or T2w MRI scans, which underlines that 68Ga-FAPI PET signalling is not a surrogate marker of MRI sequences but an independent signal.

Assessing the influence of the menstrual cycle on APT CEST-MRI in the human breast.

PURPOSE: In fibroglandular breast tissue, conventional dynamic contrast-enhanced MR-mammography is known to be affected by water content changes during the menstrual cycle. Likewise, amide proton transfer (APT) chemical exchange saturation transfer (CEST)-MRI might be inherently prone to the menstrual cycle, as CEST signals are indirectly detected via the water signal. The purpose of this study was to investigate the influence of the menstrual cycle on APT CEST-MRI in fibroglandular breast tissue. METHOD: Ten healthy premenopausal women (19-34 years) were included in this IRB approved prospective study and examined twice during their menstrual cycle. Examination one and two were performed during the first half (day 2-8) and the second half (day 15-21) of the menstrual cycle, respectively. As a reference for the APT signal in malignant breast tumor tissue, previously reported data of nine breast cancer patients were included in this study. CEST-MRI (B1 = 0.7µT) was performed on a 7 T whole-body scanner followed by a multi-Lorentzian fit analysis. The APT signal was corrected for B0/B1-field inhomogeneities, fat signal contribution, and relaxation effects of the water signal and evaluated in the fibroglandular breast tissue. Intra-individual APT signal differences between examination one and two were compared using the Wilcoxon signed-rank test. The level of significance was set at p < 0.05. RESULTS: The APT signal showed no significant difference in the fibroglandular breast tissue of healthy premenopausal volunteers throughout the menstrual cycle (p = 1.00) (examination 1 vs. examination 2: mean and standard deviation = 3.24 ± 0.68%Hz vs. 3.30 ± 0.73%Hz, median and IQR = 3.36%Hz and 0.87%Hz vs. 3.38%Hz and 0.71%Hz). CONCLUSION: The present study provides an important basis for the clinical application of APT CEST-MRI as an additional contrast mechanism in MR-mammography, as menstrual cycle-related APT signal fluctuations seem to be negligible compared to the APT signal increase in breast cancer tissue.

Relaxation-compensated CEST (chemical exchange saturation transfer) imaging in breast cancer diagnostics at 7T.

PURPOSE: To investigate whether fat-corrected and relaxation-compensated amide proton transfer (APT) and guanidyl CEST-MRI enables the detection of signal intensity differences between breast tumors and normal-appearing fibroglandular tissue in patients with newly-diagnosed breast cancer. METHOD: Ten patients with newly-diagnosed breast cancer and seven healthy volunteers were included in this prospective IRB-approved study. CEST-MRI was performed on a 7 T-whole-body scanner followed by a multi-Lorentzian fit analysis. APT and guanidyl CEST signal intensities were quantified in the tumor and in healthy fibroglandular tissue after correction of B0/B1-field inhomogeneities, fat signal contribution, T1- and T2-relaxation; signal intensity differences of APT and guanidyl resonances were compared using Mann-Whitney-U-tests. Pearson correlations between tumor CEST signal intensities and the proliferation index Ki-67 were performed. RESULTS: APT CEST signal in tumor tissue (6.70 ±â€¯1.38%Hz) was increased compared to normal-appearing fibroglandular tissue of patients (3.56 ±â€¯0.54%Hz, p = 0.001) and healthy volunteers (3.70 ±â€¯0.68%Hz, p = 0.001). Further, a moderate positive correlation was found between the APT signal and the proliferation index Ki-67 (R2 = 0.367, r = 0.606, p = 0.11). Guanidyl CEST signal was also increased in tumor tissue (5.24 ±â€¯1.85%Hz) compared to patients' (2.42 ±â€¯0.45%Hz, p = 0.006) and volunteers' (2.36 ±â€¯0.54%Hz, p < 0.001) normal-appearing fibroglandular tissue and a positive correlation with the Ki-67 level was observed (R2 = 0.365, r = 0.604, p = 0.11). APT and guanidyl CEST signal in normal-appearing fibroglandular tissue was not different between patients and healthy volunteers (p = 0.88; p = 0.93). CONCLUSION: Relaxation-compensated and fat-corrected CEST-MRI allowed a non-invasive differentiation of breast cancer and normal-appearing breast tissue. Thus, this approach represents a contrast agent-free method that may help to increase diagnostic accuracy in MR-mammography.

Dataset of voxelwise correlated signal values of ADC, rCBV and FAP-specific PET of 13 Glioblastoma patients.

This dataset is based on multimodal MRI and FAP-specific PET/CT Imaging applied to 13 patients with histologically proven glioblastomas. Imaging Data was processed using Medical Imaging Interaction Toolkit (MITK) software. MRI images (contrast enhanced T1w, T2w/FLAIR, ADC, rCBV) were co-registrated with FAP-specific PET images. T2w/FLAIR hyperintensities and contrast enhancing lesions were segmented manually. Necrotic areas were segmented manually and subtracted from T2w/FLAIR hyperintensities and contrast enhancing lesions. Voxelwise ADC/rCBV and PET signal intensities in projection on T2w/FLAIR hyperintensities and contrast enhancing lesions were extracted using the pixel dumper function of the MITK software and stored as excel-files. The data presented in this article has been analysed and described in the article FAP-specific "PET signaling shows a moderately positive correlation with relative CBV and no correlation with ADC in 13 IDH wildtype Glioblastomas" published in the European Journal of Radiology.

FAP-specific PET signaling shows a moderately positive correlation with relative CBV and no correlation with ADC in 13 IDH wildtype glioblastomas.

OBJECTIVES: Targeting Fibroblast Activation Protein (FAP) is a new approach for glioblastoma imaging. In a recent pilot study glioblastomas showed elevated tracer uptake with high intratumoral heterogeneity in projection on the corresponding T2w/FLAIR and contrast enhanced MRI lesions. In this study, we correlated FAP-specific signaling with apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) signals in MRI to further characterize the significance of FAP uptake. METHODS: Clinical PET/CT scans of 13 glioblastoma patients were performed post i. v. administration of 68Ga-labelled-FAP-specific tracer molecules. PET- and corresponding MRI-scans were co-registrated. 3d volumetric segmentations were performed of T2w/FLAIR lesions and contrast enhancing lesions within co-registrated MRI slides. Signal intensity values of FAP-specific PET signaling, ADC and rCBV were analyzed for their pixel wise correlation in each patient. Pooled estimates of the correlation coefficients were calculated by using the Fisher z-transformation. RESULTS: FAP-specific PET signals showed a moderately positive correlation with rCBV values which is more pronounced within the T2w/FLAIR lesion (pooled correlation 0,229) than in the contrast enhancing tumor region (pooled correlation 0.09). FAP-specific PET signals showed no correlation with ADC values. CONCLUSIONS: The moderately positive correlation of FAP-specific signals with rCBV values in MRI indicates that FAP-signaling is not independent from perfusion, but also does not only reflect intratumoral perfusion differences. The missing correlation of FAP-specific signals with ADC indicates that FAP-specific imaging does not reflect cell density, but the spot-like expression of FAP in glioblastomas. The clinical value of FAP-specific imaging needs further investigation.

A novel normalization for amide proton transfer CEST MRI to correct for fat signal-induced artifacts: application to human breast cancer imaging.

PURPOSE: The application of amide proton transfer (APT) CEST MRI for diagnosis of breast cancer is of emerging interest. However, APT imaging in the human breast is affected by the ubiquitous fat signal preventing a straightforward application of existing acquisition protocols. Although the spectral region of the APT signal does not coincide with fat resonances, the fat signal leads to an incorrect normalization of the Z-spectrum, and therefore to distorted APT effects. In this study, we propose a novel normalization for APT-CEST MRI that corrects for fat signal-induced artifacts in the postprocessing without the need for application of fat saturation schemes or water-fat separation approaches. METHODS: The novel normalization uses the residual signal at the spectral position of the direct water saturation to estimate the fat contribution. A comprehensive theoretical description of the normalization for an arbitrary phase relation of the water and fat signal is provided. Functionality and applicability of the proposed normalization was demonstrated by in vitro and in vivo experiments. RESULTS: In vitro, an underestimation of the conventional APT contrast of approximately -1.2% per 1% fat fraction was observed. The novel normalization yielded an APT contrast independent of the fat contribution, which was also independent of the water-fat phase relation. This allowed APT imaging in patients with mamma carcinoma corrected for fat signal contribution, field inhomogeneities, spillover dilution, and water relaxation effects. CONCLUSION: The proposed normalization increases the specificity of APT imaging in tissues with varying fat content and represents a time-efficient and specific absorption rate-efficient alternative to fat saturation and water-fat separation approaches.