Dataset Information

[¹⁸F]-Alfatide PET imaging of integrin αvβ3 for the non-invasive quantification of liver fibrosis.

ABSTRACT:

Background & aims

The vitronectin receptor integrin αvβ3 drives fibrogenic activation of hepatic stellate cells (HSCs). Molecular imaging targeting the integrin αvβ3 could provide a non-invasive method for evaluating the expression and the function of the integrin αvβ3 on activated HSCs (aHSCs) in the injured liver. In this study, we sought to compare differences in the uptake of [¹⁸F]-Alfatide between normal and injured liver to evaluate its utility for assessment of hepatic fibrogenesis.

Methods

PET with [¹⁸F]-Alfatide, non-enhanced CT, histopathology, immunofluorescence staining, immunoblotting and gene analysis were performed to evaluate and quantify hepatic integrin αvβ3 levels and liver fibrosis progression in mouse models of fibrosis (carbon tetrachloride [CCl₄] and bile duct ligation [BDL]). The liver AUC divided by the blood AUC over 30 min was used as an integrin αvβ3-PET index to quantify fibrosis progression. Ex vivo analysis of frozen liver tissue from patients with fibrosis and cirrhosis verified the animal findings.

Results

Fibrotic mouse livers showed enhanced [¹⁸F]-Alfatide uptake and retention compared to control livers. The radiotracer was demonstrated to bind specifically with integrin αvβ3, which is mainly expressed on aHSCs. Autoradiography and histopathology confirmed the PET imaging results. Further, the mRNA and protein level of integrin αvβ3 and its signaling complex were higher in CCl₄ and BDL models than controls. The results obtained from analyses on human fibrotic liver sections supported the animal findings.

Conclusions

Imaging hepatic integrin αvβ3 with PET and [¹⁸F]-Alfatide offers a potential non-invasive method for monitoring the progression of liver fibrosis.

Lay summary

Integrin αvβ3 expression on activated hepatic stellate cells (aHSCs) is associated with HSC proliferation during hepatic fibrogenesis. Herein, we show that a radioactive tracer, [¹⁸F]-Alfatide, binds to integrin αvβ3 with high affinity and specificity. [¹⁸F]-Alfatide could thus be used as a non-invasive imaging biomarker to track hepatic fibrosis progression.

SUBMITTER: Shao T

PROVIDER: S-EPMC7363052 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:18F-alfatide II has been proven to have excellent clinical translational potential. In this study, we investigated 18F-alfatide II for identifying breast cancer and compared the performances between 18F-alfatide II and 18F-FDG. Methods: Forty-four female patients with suspected primary breast cancer were recruited. PET/CT images using 18F-alfatide II and 18F-FDG were acquired within 7 d. Tracer uptake in breast lesions was evaluated by visual analysis, and semiquantitative analysis with SUVmax and SUVmean Results: Forty-two breast cancer lesions and 11 benign breast lesions were confirmed by histopathology in 44 patients. Both 18F-alfatide II and 18F-FDG had higher uptake in breast cancer lesions than in benign breast lesions (P < 0.05 for 18F-alfatide II, P < 0.05 for 18F-FDG). The area under the curve of 18F-alfatide II was slightly less than that of 18F-FDG. Both 18F-alfatide II and 18F-FDG had high sensitivity (88.1% vs. 90.5%), high positive predictive value (88.1% vs. 88.4%), moderate specificity (54.5% vs. 54.5%), and moderate negative predictive value (54.5% vs. 60.0%) for differentiating breast cancer from benign breast lesions. By combining 18F-alfatide II and 18F-FDG, the sensitivity and negative predictive value significantly increased to 97.6% and 85.7%, respectively, with positive predictive value slightly increased to 89.1% and no change to the specificity (54.5%). The uptake of 18F-alfatide II (SUVmax: 3.77 ± 1.78) was significantly lower than that of 18F-FDG (SUVmax: 7.37 ± 4.48) in breast cancer lesions (P < 0.05). 18F-alfatide II uptake in triple-negative subtype was significantly lower than that in luminal A and luminal B subtypes. By contrast, human epidermal growth factor receptor-2 (HER-2)-overexpressing subtype had higher 18F-FDG uptake than the other 3 subtypes. There were 8 breast cancer lesions with higher 18F-alfatide II uptake than 18F-FDG uptake, which all had a common characteristic that HER-2 expression was negative and estrogen receptor expression was strongly positive. Conclusion: 18F-alfatide II is suitable for clinical use in breast cancer patients. 18F-alfatide II is of good performance, but not superior to 18F-FDG in identifying breast cancer. 18F-alfatide II may have superiority to 18F-FDG in detecting breast cancer with strongly positive estrogen receptor expression and negative HER-2 expression.

Project description:PurposeThe tau tracer [18F]AV1451, also known as flortaucipir, is a promising ligand for imaging tau accumulation in Alzheimer's disease (AD). Most of the previous studies have quantified tau load using standardized uptake value ratios (SUVr) derived from a static [18F]AV1451 scan. SUVr may, however, be flow dependent and, especially for longitudinal studies, should be validated against a fully quantitative approach. The objective of this study was to identify the optimal tracer kinetic model for measuring tau load using [18F]AV1451.ProceduresFollowing intravenous injection of 225 ± 16 MBq [18F]AV1451, 130 min dynamic PET scans were performed in five biomarker confirmed AD patients and five controls. Arterial blood sampling was performed to obtain a metabolite-corrected plasma input function. Next, regional time-activity curves were generated using PVElab software. These curves were analysed using several pharmacokinetic models.ResultsThe reversible single tissue compartment model (1T2k_VB) was the preferred model for all but one control. For AD patients, however, model preference shifted towards a reversible two tissue compartmental model (2T4k_VB). The simplified reference tissue model (SRTM) derived binding potential (BPND) showed good correlation (AD: r 2 = 0.87, slope = 1.06; controls: r 2 = 0.87, slope = 0.86) with indirect plasma input binding (distribution volume ratio-1). Standardized uptake value ratios (80-100 min) correlated well with DVR (r 2 = 0.93, slope = 1.07) and SRTM-derived BPND (r 2 = 0.84, slope = 0.95). In addition, regional differences in tracer binding between subject groups in different tau-specific regions were observed.ConclusionsModel preference of [18F]AV1451 appears to depend on subject status and, in particular, VT. The relationship between model preference and VT suggests that (higher) tau load may be reflected by a second tissue compartment. Nevertheless, consistent results can be obtained using a 2T4k_VB model. In addition, SRTM can be used to derive BPND.

Project description:BackgroundThe standard MR Dixon-based attenuation correction (AC) method in positron emission tomography/magnetic resonance (PET/MR) imaging segments only the air, lung, fat and soft-tissues (4-class), thus neglecting the highly attenuating bone tissues and affecting quantification in bones and adjacent vessels. We sought to address this limitation by utilizing the distinctively high bone uptake rate constant Ki expected from 18F-Sodium Fluoride (18F-NaF) to segment bones from PET data and support 5-class hybrid PET/MR-driven AC for 18F-NaF and 18F-Fluorodeoxyglucose (18F-FDG) PET/MR cardiovascular imaging.MethodsWe introduce 5-class Ki/MR-AC for (i) 18F-NaF studies where the bones are segmented from Patlak Ki images and added as the 5th tissue class to the MR Dixon 4-class AC map. Furthermore, we propose two alternative dual-tracer protocols to permit 5-class Ki/MR-AC for (ii) 18F-FDG-only data, with a streamlined simultaneous administration of 18F-FDG and 18F-NaF at 4:1 ratio (R4:1), or (iii) for 18F-FDG-only or both 18F-FDG and 18F-NaF dual-tracer data, by administering 18F-NaF 90 minutes after an equal 18F-FDG dosage (R1:1). The Ki-driven bone segmentation was validated against computed tomography (CT)-based segmentation in rabbits, followed by PET/MR validation on 108 vertebral bone and carotid wall regions in 16 human volunteers with and without prior indication of carotid atherosclerosis disease (CAD).ResultsIn rabbits, we observed similar (< 1.2% mean difference) vertebral bone 18F-NaF SUVmean scores when applying 5-class AC with Ki-segmented bone (5-class Ki/CT-AC) vs CT-segmented bone (5-class CT-AC) tissue. Considering the PET data corrected with continuous CT-AC maps as gold-standard, the percentage SUVmean bias was reduced by 17.6% (18F-NaF) and 15.4% (R4:1) with 5-class Ki/CT-AC vs 4-class CT-AC. In humans without prior CAD indication, we reported 17.7% and 20% higher 18F-NaF target-to-background ratio (TBR) at carotid bifurcations wall and vertebral bones, respectively, with 5- vs 4-class AC. In the R4:1 human cohort, the mean 18F-FDG:18F-NaF TBR increased by 12.2% at carotid bifurcations wall and 19.9% at vertebral bones. For the R1:1 cohort of subjects without CAD indication, mean TBR increased by 15.3% (18F-FDG) and 15.5% (18F-NaF) at carotid bifurcations and 21.6% (18F-FDG) and 22.5% (18F-NaF) at vertebral bones. Similar TBR enhancements were observed when applying the proposed AC method to human subjects with prior CAD indication.ConclusionsKi-driven bone segmentation and 5-class hybrid PET/MR-driven AC is feasible and can significantly enhance 18F-NaF and 18F-FDG contrast and quantification in bone tissues and carotid walls.

Project description:Invasive lobular carcinoma (ILC) demonstrates lower conspicuity on 18F-FDG PET than the more common invasive ductal carcinoma. Other molecular imaging methods may be needed for evaluation of this malignancy. As ILC is nearly always (95%) estrogen receptor (ER)-positive, ER-targeting PET tracers such as 16α-18F-fluoroestradiol (18F-FES) may have value. We reviewed prospective trials at Memorial Sloan Kettering Cancer Center using 18F-FES PET/CT to evaluate metastatic ILC patients with synchronous 18F-FDG and 18F-FES PET/CT imaging, which allowed a head-to-head comparison of these 2 PET tracers. Methods: Six prospective clinical trials using 18F-FES PET/CT in patients with metastatic breast cancer were performed at Memorial Sloan Kettering Cancer Center from 2008 to 2019. These trials included 92 patients, of whom 14 (15%) were of ILC histology. Seven of 14 patients with ILC had 18F-FDG PET/CT performed within 5 wk of the research 18F-FES PET/CT and no intervening change in management. For these 7 patients, the 18F-FES and 18F-FDG PET/CT studies were analyzed to determine the total number of tracer-avid lesions, organ systems of involvement, and SUVmax of each organ system for both tracers. Results: In the 7 comparable pairs of scans, there were a total of 254 18F-FES-avid lesions (SUVmax, 2.6-17.9) and 111 18F-FDG-avid lesions (SUVmax, 3.3-9.9) suggestive of malignancy. For 5 of 7 (71%) ILC patients, 18F-FES PET/CT detected more metastatic lesions than 18F-FDG PET/CT. In the same 5 of 7 patients, the SUVmax of 18F-FES-avid lesions was greater than the SUVmax of 18F-FDG-avid lesions. One patient had 18F-FES-avid metastases with no corresponding 18F-FDG-avid metastases. There were no patients with 18F-FDG-avid distant metastases without 18F-FES-avid distant metastases, although in one patient liver metastases were evident on 18F-FDG but not on 18F-FES PET. Conclusion: 18F-FES PET/CT compared favorably with 18F-FDG PET/CT for detection of metastases in patients with metastatic ILC. Larger prospective trials of 18F-FES PET/CT in ILC should be considered to evaluate ER-targeted imaging for clinical value in patients with this histology of breast cancer.