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Purpose [ 18 F]NaF PET has become an increasingly important tool in clinical practice toward understanding and evaluating diseases and conditions in which bone metabolism is disrupted. Full kinetic analysis using nonlinear regression (NLR) with a two-tissue compartment model to determine the net rate of influx ( K i ) of [ 18 F]NaF is considered the gold standard for quantification of [ 18 F]NaF uptake. However, dynamic scanning often is impractical in a clinical setting, leading to the development of simplified semi-quantitative parameters. This systematic review investigated which uptake parameters have been used to evaluate bone disorders and how they have been validated to measure disease activity. Methods A literature search (in PubMed, Embase.com, and Clarivate Analytics/Web of Science Core Collection) was performed up to 28th November 2023, in collaboration with an information specialist. Each database was searched for relevant literature regarding the use of [ 18 F]NAF PET/CT to measure disease activity in bone-related disorders. The main aim was to explore whether the reported semi-quantitative uptake values were validated against full kinetic analysis. A second aim was to investigate whether the chosen uptake parameter correlated with a disease-specific outcome or marker, validating its use as a clinical outcome or disease marker. Results The initial search included 1636 articles leading to 92 studies spanning 29 different bone-related conditions in which [ 18 F]NaF PET was used to quantify [ 18 F]NaF uptake. In 12 bone-related disorders, kinetic analysis was performed and compared with simplified uptake parameters. SUV mean (standardized uptake value) and SUV max were used most frequently, though normalization of these values varied greatly between studies. In some disorders, various studies were performed evaluating [ 18 F]NaF uptake as a marker of bone metabolism, but unfortunately, not all studies used this same approach, making it difficult to compare results between those studies. Conclusion When using [ 18 F]NaF PET to evaluate disease activity or treatment response in various bone-related disorders, it is essential to detail scanning protocols and analytical procedures. The most accurate outcome parameter can only be obtained through kinetic analysis and is better suited for research. Simplified uptake parameters are better suited for routine clinical practice and repeated measurements.

Background Coronary artery disease (CAD) is a major contributor to cardiovascular events in individuals with diabetes. Quantification of coronary atherosclerotic burden is now feasible from coronary computed tomography angiography (CTA) whereas positron emission tomography (PET) enables quantitative assessment of myocardial perfusion. We studied the prognostic implications of quantitatively measured coronary plaque burden and myocardial perfusion in diabetic vs. non-diabetic patients with suspected CAD. Methods In this observational cohort study, 1311 symptomatic patients with suspected CAD underwent coronary CTA and [ 15 O]H 2 O PET perfusion imaging. Coronary plaque burden was quantified using artificial intelligence–based analysis and reported as percent atheroma volume (PAV). Myocardial perfusion was assessed as regional stress myocardial blood flow (sMBF), with abnormal perfusion defined as ≥ 2 adjacent segments with sMBF < 2.3 ml/g/min. The composite endpoint was all-cause death, myocardial infarction (MI), or unstable angina pectoris (UAP) over 7 years. Results Among the 1311 patients, 251 (19%) had diabetes and 134 (10%) experienced an adverse event during follow-up. The annual event rate was low (0.8% [95% CI 0.6–1.1%]) in non-diabetic patients with normal myocardial perfusion and increased significantly with the presence of either diabetes (2.3% [95% CI 1.4–3.8%]), abnormal perfusion (2.6% [95% CI 2.1–3.3%]), or both (3.2% [95% CI 2.1–4.8%]) ( p  < 0.001). Among patients with normal myocardial perfusion, those with diabetes had two-fold PAV as compared with non-diabetic individuals (median 8.2% vs. 4.1%, p  < 0.001). In multivariable Cox regression models, both PAV (HR 1.03 [95% CI 1.01–1.05] per 1% increase, p  < 0.001) and regional sMBF (HR 1.04 [95% CI 1.01–1.07] per 0.1 ml/g/min decrease, p  = 0.016) were independent predictors of adverse outcome in non-diabetic patients. In diabetic patients, only PAV (HR 1.04 [95% CI 1.01–1.07], p  = 0.014) was predictive, whereas sMBF was not. Conclusions Coronary atherosclerotic plaque burden appears as an important predictor of long-term cardiovascular outcomes both in diabetic and non-diabetic patients. In patients with diabetes, normal myocardial perfusion does not necessarily imply low event risk, partly attributable to higher coronary plaque burden. Quantitative imaging methods for detailed CAD phenotyping shed light on the complex relationship between diabetes and clinical outcomes. Graphical abstract

Background Diagnostic and treatment response criteria for the JAK2/CALR/MPL mutation-related myeloproliferative neoplasms (MPNs) are largely based on bone marrow (BM) biopsy results. However, these biopsies have several limitations, such as the risk of sampling error. Also, the prognostic impact of BM abnormalities is largely unclear. Although not currently used in clinical practice, imaging techniques might offer additional information. In this review, we investigated the value of BM, liver, and spleen imaging for diagnosis, prognostication, and response monitoring of the JAK2/CALR/MPL mutation-related MPNs (i.e. essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF)). Methods A systematic literature search was performed via PubMed, Embase and the Cochrane Library up to 2020 March 26th. Of 5505 identified records, 55 publications met the eligibility criteria (i.e. containing original data on the imaging appearance of BM, spleen, or liver in adult ET, PV, or MF patients, published in a peer-reviewed journal, written in English). Results Many explorative studies described imaging features, sometimes with comparisons to clinical characteristics. Studies reporting measures of diagnostic accuracy included 1) splenic transient elastography to predict BM fibrosis grade in MF, 2) dynamic contrast-enhanced MRI to discern MF patients from ET patients and healthy controls, and 3) 18-fluorodeoxyglucose PET to detect residual disease after stem cell transplantation in MF. The diagnostic accuracies of radiography and 99m Tc-colloid scintigraphy were derived from several other articles. Except for the study on 18-fluorodeoxyglucose PET, we established substantial concerns regarding risk of bias and applicability across these studies, using the QUADAS-2 tool. Three publications described a correlation between imaging results and prognosis, of which one quantified the effect. Conclusions Based on current data, MRI (T1-weighted/STIR, Dixon) seems especially promising for the evaluation of BM fat content - and indirectly cellularity/fibrosis - in MF, and possibly for estimating BM cellularity in ET/PV. 18-fluorodeoxyglucose and 18-fluorothymidine PET/CT might be useful for evaluating BM fibrosis, with good reported accuracy of the former for the diagnosis of residual disease. Further research on these and other techniques is warranted to determine their exact value. Future researchers should improve methodology and focus on evaluation of diagnostic accuracy and prognostic implications of results.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic bone disorder characterized by episodic flare-ups in connective tissue, which are frequently followed by the formation of heterotopic ossification. The absence of available plasma-soluble biomarkers for flare-ups or heterotopic bone formation poses severe challenges to the monitoring of disease activity to measure or predict disease progression. Recently, 18-fluor-sodium fluoride positron emission tomography/computed tomography ([18F]NaF PET/CT) was introduced as a potential marker for ossifying FOP activity. This review discusses the pharmacokinetics of [18F]NaF in relation to the pathophysiology of FOP, and its use as a marker of local bone metabolism in a variety of bone-related disorders. In addition, the review specifically addresses the applicability of [18F]NaF PET/CT imaging in FOP as a monitoring modality.

Background: Symptomatic patients with unilateral obstructive coronary artery disease (CAD) identified by coronary computed tomography angiography (CCTA), involving either the right or left coronary artery, typically undergo per-protocol bilateral coronary visualization during invasive coronary angiography (ICA). However, a selective visualization approach may be sufficient. Objectives: The objectives of this study were to assess the accuracy of CCTA in excluding hemodynamically significant coronary stenosis in patients with unilateral CAD and to evaluate whether a CCTA-guided selective ICA strategy can reduce procedure time and contrast agent use. Methods: In this cross-sectional cohort study, 454 patients with clinically suspected stable CAD who underwent CCTA prior to ICA were included. The study population consisted of 190 patients with unilateral obstructive CAD, defined as ≥50% diameter stenosis on CCTA, and an absence of obstructive CAD on the contralateral side. ICA with invasive functional assessment was used as the reference standard. Results: CCTA demonstrated a high accuracy, 97.4% (95% CI: 94–99%), in excluding hemodynamically significant disease in the contralateral arteries without obstructive CAD. Compared to the conventional ICA approach, a CCTA-guided selective visualization strategy resulted in significant reductions in procedure time and contrast agent usage: procedure time and contrast agent usage were reduced by 27% (95% CI: 12.1–47.5%) and 46.8% (95% CI: 27.5–67.0%), respectively. Conclusions: In patients with unilateral obstructive CAD identified by CCTA, a CCTA-guided selective ICA visualization strategy is highly accurate in ruling out hemodynamically significant CAD on the contralateral side. Additionally, this unilateral ICA approach has the potential to reduce both contrast agent usage and procedure time compared to the conventional bilateral visualization strategy.

Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are invasive techniques used to evaluate the hemodynamic significance of coronary artery stenosis. These methods have been validated through perfusion imaging and clinical trials. New invasive pressure ratios that do not require hyperemia have recently emerged, and it is essential to confirm their diagnostic efficacy. The aim of this study was to validate the resting full-cycle ratio (RFR) and the diastolic pressure ratio (dPR), against [ 15 O]H 2 O positron emission tomography (PET) imaging. A total of 129 symptomatic patients with an intermediate risk of coronary artery disease (CAD) were included. All patients underwent cardiac [ 15 O]H 2 O PET with quantitative assessment of resting and hyperemic myocardial perfusion. Within a 2 week period, coronary angiography was performed. Intracoronary pressure measurements were obtained in 320 vessels and RFR, dPR, and FFR were computed. PET derived regional hyperemic myocardial blood flow (hMBF) and myocardial perfusion reserve (MPR) served as reference standards. In coronary arteries with stenoses (43%, 136 of 320), the overall diagnostic accuracies of RFR, dPR, and FFR did not differ when PET hyperemic MBF < 2.3 ml min −1 (69.9%, 70.6%, and 77.1%, respectively) and PET MPR < 2.5 (70.6%, 71.3%, and 66.9%, respectively) were considered as the reference for myocardial ischemia. Non-significant differences between the areas under the receiver operating characteristic (ROC) curve were found between the different indices. Furthermore, the integration of FFR with RFR (or dPR) does not enhance the diagnostic information already achieved by FFR in the characterization of ischemia via PET perfusion. In conclusion, the novel non-hyperemic pressure ratios, RFR and dPR, have a diagnostic performance comparable to FFR in assessing regional myocardial ischemia. These findings suggest that RFR and dPR may be considered as an FFR alternative for invasively guiding revascularization treatment in symptomatic patients with CAD.

Noninvasive assessment of coronary artery disease remains a challenging task, with a large armamentarium of diagnostic modalities. Myocardial perfusion imaging (MPI) is widely used for this purpose whereby cardiac positron emission tomography (PET) is considered the gold standard. Next to relative radiotracer distribution, PET allows for measurement of absolute myocardial blood flow. This quantification of perfusion improves diagnostic accuracy and prognostic value. Cardiac hybrid imaging relies on the fusion of anatomical and functional imaging using coronary computed tomography angiography and MPI, respectively, and provides incremental value as compared with either stand-alone modality.

Early recognition of viable myocardium after acute myocardial infarction (AMI) is of clinical relevance, since affected segments have the potential of functional recovery. Delayed contrast-enhanced magnetic resonance imaging (DCE-CMR) has been validated extensively for the detection of viable myocardium. An alternative parameter for detecting viability is the perfusable tissue index (PTI), derived using [15O]H2O positron emission tomography (PET), which is inversely related to the extent of myocardial scar (non-perfusable tissue). The aim of the present study was to investigate the predictive value of PTI on recovery of LV function as compared to DCE-CMR in patients with AMI, after successful percutaneous coronary intervention (PCI). Thirty-eight patients with ST elevation myocardial infarction (STEMI) successfully treated by PCI were prospectively recruited. Subjects were examined 1 week and 3 months (mean follow-up time: 97 ± 10 days) after AMI using [15O]H2O PET and DCE-CMR to assess PTI, regional function and scar. Viability was defined as recovery of systolic wall thickening ≥3.0 mm at follow-up by use of CMR. A total of 588 segments were available for serial analysis. At baseline, 180 segments were dysfunctional and exhibited DCE. Seventy-three (41%) of these dysfunctional segments showed full recovery during follow-up (viable), whereas 107 (59%) segments remained dysfunctional (nonviable). Baseline PTI of viable segments was 0.94 ± 0.09 and was significantly higher compared to nonviable segments (0.80 ± 0.13, P < .001). The optimal cut-off value for PTI was ≥0.85 with a sensitivity of 85% and specificity of 72%, and an area under the curve (AUC) of 0.82. In comparison, a cut-off value of <32% for the extent of DCE resulted in a sensitivity of 72% and a specificity of 69%, and an AUC of 0.75 (AUC PTI vs DCE P = .14). Assessment of myocardial viability shortly after reperfused AMI is feasible using PET. PET-derived PTI yields a good predictive value for the recovery of LV function in PCI-treated STEMI patients, in excellent agreement with DCE-CMR.

Background There has been increasing interest in quantitative myocardial blood flow (MBF) imaging over the last years and it is expected to become a routinely used technique in clinical practice. Positron emission tomography (PET) using [ 15 O]H 2 O is the established gold standard for quantification of MBF in vivo. A fundamental issue when performing quantitative MBF imaging is to define the limits of MBF in a clinically suitable population. The aims of the present study were to determine the limits of MBF and to determine the relationship among coronary artery disease (CAD) risk factors, gender and MBF in a predominantly symptomatic patient cohort without significant CAD. Methods A total of 128 patients (mean age 54 ± 10 years, 50 men) with a low to intermediate pretest likelihood of CAD were referred for noninvasive evaluation of CAD using a hybrid PET/computed tomography (PET/CT) scanner. MBF was quantified with [ 15 O]H 2 O at rest and during adenosine-induced hyperaemia. Obstructive CAD was excluded in these patients by means of invasive or CT-based coronary angiography. Results Global average baseline MBF values were 0.91 ± 0.34 and 1.09 ± 0.30  ml·min −1 ·g −1 (range 0.54–2.35  and 0.59–2.75 ml·min −1 ·g −1 ) in men and women, respectively ( p  < 0.01). However, no gender-dependent difference in baseline MBF was seen following correction for rate–pressure product (0.98 ± 0.45 and 1.09 ± 0.30 ml·min −1 ·g −1 in men and women, respectively; p  = 0.08). Global average hyperaemic MBF values were 3.44 ± 1.20 ml·min −1 ·g −1 in the whole study population, and 2.90 ± 0.85 and 3.78 ± 1.27 ml·min −1 ·g −1 (range 1.52–5.22 and 1.72–8.15 ml·min −1 ·g −1 ) in men and women, respectively ( p  < 0.001). Multivariate analysis identified male gender, age and body mass index as having an independently negative impact on hyperaemic MBF. Conclusion Gender, age and body mass index substantially influence reference values and should be corrected for when interpreting hyperaemic MBF values.

Patients with coronary artery disease and/or type 2 diabetes mellitus (DM) generally exhibit more epicardial adipose tissue (EAT) than healthy controls. Recently, it has been proposed that EAT affects vascular function and structure by secreting proinflammatory and vasoactive substances, thereby potentially contributing to the development of cardiovascular disease. In the present study, the interrelation of EAT, coronary vasomotor function, and coronary artery calcium was investigated in patients with and without DM, who were evaluated for coronary artery disease. Myocardial blood flow (MBF) was assessed at rest and during adenosine-induced hyperemia using [15O]-water positron emission tomography combined with computed tomography to quantify coronary artery calcium and EAT in 199 patients (46 with DM). In this cohort (mean age 58 ± 10 years), the patients with DM had a greater body mass index, heart rate, and systolic blood pressure at rest (all p <0.05). Coronary artery calcium and the EAT volumes were comparable between those with and without DM. Both patient groups showed comparable MBF at rest and coronary vascular resistance. A lower hyperemic MBF and coronary flow reserve (CFR) and greater hyperemic coronary vascular resistance (all p <0.05) was observed in the patients with DM. A pooled analysis showed a positive association of EAT volume with hyperemic coronary vascular resistance but not with the MBF at rest, hyperemic MBF, or coronary vascular resistance at rest. In the group analysis, the EAT volume was inversely associated with hyperemic MBF (r = −0.16, p = 0.05) and CFR (r = −0.17, p = 0.04) and positively with hyperemic coronary vascular resistance (r = 0.26, p = 0.002) only in patients without DM. Multivariate regression analysis, adjusted for age, gender, and body mass index, showed an independent association between the EAT volume and hyperemic MBF (β = −0.16, p = 0.02), CFR (β = −0.16, p = 0.04), and hyperemic coronary vascular resistance (β = 0.25, p <0.001) in the non-DM group. In conclusion, these results suggest a role for EAT in myocardial microvascular dysfunction; however, once DM has developed, other factors might be more dominant in contributing to impaired myocardial microvascular dysfunction.