Hybrid PET- and MR-driven attenuation correction for enhanced ¹⁸F-NaF and ¹⁸F-FDG quantification in cardiovascular PET/MR imaging

Background: The 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. Methods: We 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). Results: In 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. Conclusions: Ki-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

Hybrid PET/MR Kernelised Expectation Maximisation Reconstruction for Improved Image-Derived Estimation of the Input Function from the Aorta of Rabbits

Positron emission tomography (PET) provides simple noninvasive imaging biomarkers for multiple human diseases which can be used to produce quantitative information from single static images or to monitor dynamic processes. Such kinetic studies often require the tracer input function (IF) to be measured but, in contrast to direct blood sampling, the image-derived input function (IDIF) provides a noninvasive alternative technique to estimate the IF. Accurate estimation can, in general, be challenging due to the partial volume effect (PVE), which is particularly important in preclinical work on small animals. The recently proposed hybrid kernelised ordered subsets expectation maximisation (HKEM) method has been shown to improve accuracy and contrast across a range of different datasets and count levels and can be used on PET/MR or PET/CT data. In this work, we apply the method with the purpose of providing accurate estimates of the aorta IDIF for rabbit PET studies. In addition, we proposed a method for the extraction of the aorta region of interest (ROI) using the MR and the HKEM image, to minimise the PVE within the rabbit aortic region—a method which can be directly transferred to the clinical setting. A realistic simulation study was performed with ten independent noise realisations while two, real data, rabbit datasets, acquired with the Biograph Siemens mMR PET/MR scanner, were also considered. For reference and comparison, the data were reconstructed using OSEM, OSEM with Gaussian postfilter and KEM, as well as HKEM. The results across the simulated datasets and different time frames show reduced PVE and accurate IDIF values for the proposed method, with 5% average bias (0.8% minimum and 16% maximum bias). Consistent results were obtained with the real datasets. The results of this study demonstrate that HKEM can be used to accurately estimate the IDIF in preclinical PET/MR studies, such as rabbit mMR data, as well as in clinical human studies. The proposed algorithm is made available as part of an open software library, and it can be used equally successfully on human or animal data acquired from a variety of PET/MR or PET/CT scanners

Length of Thromboprophylaxis in Patients Operated on for a High-Grade Glioma: A Retrospective Study.

OBJECTIVE: High-grade gliomas are associated with venous thromboembolism (VTE). This retrospective study with a parallel cohort design investigated influence of continuing prophylactic anticoagulation after discharge on rate of VTE and intracranial hemorrhage (ICH) in patients operated on for high-grade glioma. METHODS: Consecutive adult patients who underwent subtotal or gross total resection for high-grade glioma at a single institution were included. Multivariable logistic regression analysis was used to investigate the association between duration of thromboprophylaxis (dalteparin administered 21 days vs. 0-7 days) and occurrence of VTE and ICH within 21 or 90 days after surgery, corrected for known risk factors. RESULTS: Of 301 included patients, 166 received short-term thromboprophylaxis, and 135 received prolonged thromboprophylaxis. In multivariable analysis, prolonged thromboprophylaxis was not significantly associated with occurrence of VTE within 21 days (3.0% vs. 1.2%; P = 0.24) or 90 days (8.9% vs. 4.8%; P = 0.09) after surgery; however, prolonged prophylaxis was associated with occurrence of ICH (5.9% vs. 0.6%; P = 0.03). Additionally, immobility (P = 0.03) and high body mass index (P = 0.02) were associated with occurrence of VTE. CONCLUSIONS: Prophylactic anticoagulation for 21 days postoperatively was not associated with a decreased rate of VTE compared with thromboprophylaxis until discharge. ICH was more common with prolonged thromboprophylaxis. These results provide insufficient evidence to extend duration of prophylaxis beyond hospitalization. Large-scale randomized prospective studies are needed to clarify safety, efficacy, and optimal timing of postoperative thromboprophylaxis in patients with high-grade glioma

Employing nanobodies for immune landscape profiling by PET imaging in mice

Summary: Noninvasive immunoimaging holds great potential for studying and stratifying disease as well as therapeutic efficacy. Radiolabeled single-domain antibody fragments (i.e., nanobodies) are appealing probes for immune landscape profiling, as they display high stability, rapid targeting, and excellent specificity, while allowing extremely sensitive nuclear readouts. Here, we present a protocol for radiolabeling an anti-CD11b nanobody and studying its uptake in mice by a combination of positron emission tomography imaging, ex vivo gamma counting, and autoradiography. Our protocol is applicable to nanobodies against other antigens.For complete details on the use and execution of this protocol, please see Priem et al. (2020), Senders et al. (2019), or Rashidian et al. (2017)

A systematic comparison of clinically viable nanomedicines targeting HMG-CoA reductase in inflammatory atherosclerosis

Atherosclerosis is a leading cause of worldwide morbidity and mortality whose management could benefit from novel targeted therapeutics. Nanoparticles are emerging as targeted drug delivery systems in chronic inflammatory disorders. To optimally exploit nanomedicines, understanding their biological behavior is crucial for further development of clinically relevant and efficacious nanotherapeutics intended to reduce plaque inflammation. Here, three clinically relevant nanomedicines, i.e., high-density lipoprotein ([S]-HDL), polymeric micelles ([S]-PM), and liposomes ([S]-LIP), that are loaded with the HMG-CoA reductase inhibitor simvastatin [S], were evaluated in the apolipoprotein E-deficient (Apoe(-/-)) mouse model of atherosclerosis. We systematically employed quantitative techniques, including in vivo positron emission tomography imaging, gamma counting, and flow cytometry to evaluate the biodistribution, nanomedicines' uptake by plaque-associated macrophages/monocytes, and their efficacy to reduce macrophage burden in atherosclerotic plaques. The three formulations demonstrated distinct biological behavior in Apoe(-/-)mice. While [S]-PM and [S]-LIP possessed longer circulation half-lives, the three platforms accumulated to similar levels in atherosclerotic plaques. Moreover, [S]-HDL and [S]-PM showed higher uptake by plaque macrophages in comparison to [S]-LIP, while [S]-PM demonstrated the highest uptake by Ly6C(high) monocytes. Among the three formulations, [S]-PM displayed the highest efficacy in reducing macrophage burden in advanced atherosclerotic plaques. In conclusion, our data demonstrate that [S]-PM is a promising targeted drug delivery system, which can be advanced for the treatment of atherosclerosis and other inflammatory disorders in the clinical settings. Our results also emphasize the importance of a thorough understanding of nanomedicines' biological performance, ranging from the whole body to the target cells, as well drug retention in the nanoparticles. Such systematic investigations would allow rational applications of nanomaterials', beyond cancer, facilitating the expansion of the nanomedicine horizo

International practice variation in postoperative imaging of chronic subdural hematoma patients

OBJECTIVE The value of CT scanning after burr hole surgery in chronic subdural hematoma (CSDH) patients is unclear, and practice differs between countries. At the Brigham and Women’s Hospital (BWH) in Boston, Massachusetts, neurosurgeons frequently order routine postoperative CT scans, while the University Medical Center Utrecht (UMCU) in the Netherlands does not have this policy. The aim of this study was to compare the use of postoperative CT scans in CSDH patients between these hospitals and to evaluate whether there are differences in clinical outcomes. METHODS The authors collected data from both centers for 391 age- and sex-matched CSDH patients treated with burr hole surgery between January 1, 2002, and July 1, 2016, and compared the number of postoperative scans up to 6 weeks after surgery, the need for re-intervention, and postoperative neurological condition. RESULTS BWH patients were postoperatively scanned a median of 4 times (interquartile range [IQR] 2–5), whereas UMCU patients underwent a median of 0 scans (IQR 0–1, p < 0.001). There was no significant difference in the number of re-operations (20 in the BWH vs 27 in the UMCU, p = 0.34). All re-interventions were preceded by clinical decline and no recurrences were detected on scans performed on asymptomatic patients. Patients’ neurological condition was not worse in the UMCU than in the BWH (p = 0.43). CONCLUSIONS While BWH patients underwent more scans than UMCU patients, there were no differences in clinical outcomes. The results of this study suggest that there is little benefit to routine scanning in asymptomatic patients who have undergone surgical treatment of uncomplicated CSDH and highlight opportunities to make practice more efficient