{'fraction_non_alphanumeric': 0.030947389437955476, 'fraction_numerical': 0.012478786063691724, 'mean_word_length': 4.924305144884683, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Diagnostic Role and Feasibility of 18 F-FDG PET for Assessing Takayasu Arteritis: Diagnostic Efficacy of Quantifying 18 F-FDG Uptake

Takayasu arteritis (TAK) is classified as large-vessel vasculitis caused by inflammation. It is often difficult to identify on clinical examination, and 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) plays an indispensable role in diagnosing TAK by detecting the location and grade of the inflammatory lesions. The clinical utility of 18 F-FDG PET has been established by clinical evidence, and 18 F-FDG PET was added to the Japanese national health insurance listing in April 2018. In TAK, 18 F-FDG uptake shows typical findings and is easily distinguished, except from physiological uptake. Particularly, the clinical significance of 18 F-FDG PET is that can present not only with stenosis but also without stenosis in the arteries, which means that therapeutic intervention is possible before irreversible stenosis develops in the arteries. Additionally, 18 F-FDG PET has superior diagnostic accuracy because it allows quantitative analysis using the maximum standardized uptake value. The analysis is used for the assessment of disease activity of TAK and can be utilized for therapeutic intervention in case of repeating remission during the follow-up term.

T akayasu arteritis (TAK), classified as a large-vessel vasculitis, is an inflammatory disease of unknown etiology (1). It causes stenotic or dilated lesions, predominantly in the aorta and its main branches. However, the initial diagnosis is often difficult using medical examination alone because it manifests as various symptoms without specific markers. Therefore, 18  This disease is common in young female in Asia and the Middle East than in Europe and North America (2).
Particularly, peak age of onset is the latter half of teens and early twenties in female patients (3). In Japan, more than 5000cases are registered and the number of patients increases by 200 to 400 every 3 years, however the rate of increase has been suppressed in recent years (3).
particularly from the media to the adventitia, show inflammatory cellular infiltration, necrosis of the vascular smooth muscle cells, destruction of the elastic fibers, and fibrosis.
These lead to reactive changes that cause fibrous thickening of the intima, resulting in luminal narrowing of the blood vessels.
Whereas, destruction of elastic fibers may lead to loss of blood vessel elasticity and separation between the media and adventitia, causing the development of dilated lesions such as aortic aneurysms (5).
Generally, TAK can trigger various symptoms in organs throughout the body. Clinically, its symptoms are roughly classified into systemic symptoms due to immune response (e.g., pyrexia and general malaise) and ischemic symptoms due to site of vascular stenosis. TAK used to be termed a "pulseless disease." Pulselessness in the brachial and radial arteries and a large difference in blood pressure between the right and left arms are the most common findings of this disease, which can be explained by the narrowing of the arteries.
Blood tests for the disease reveal inflammatory findings, such as elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), but there are no markers specific to the disease (6). In some cases, TAK could be diagnosed as fever of unknown origin, and a definitive diagnosis is challenging. Therefore, imaging is essential to understand the clinical presentation of the disease.

F-FDG uptake process in Takayasu arteritis
In TAK, inflammatory cells, such as white blood cells, aggregate at the sites of inflammation. Since 18 F-FDG is a glucose analog, it accumulates through the glucose transporter (GLUT).
Various types of white blood cells travel to the lesion via an immune response to antigens that are yet to be identified in this disease. In particular, T cells and natural killer cells exert a cytotoxic action, and macrophages and neutrophils stimulated by cytokines migrate, causing inflammation to spread from the media to adventitia of the blood vessels (5). GLUT1 and GLUT3 are expressed in the white blood cells (7), and the respiratory burst activated in the course of inflammation consumes abundant glucose, causing injected 18 F-FDG to be taken up into the inflammatory cells via GLUT (8).
Therefore, 18 F-FDG accumulates in proportion to the degree of inflammation. The standardized uptake value (SUV) tends to be high in neoplastic diseases but not so much in inflammatory diseases, such as TAK. This is attributable to differences in pathological activity between tumor cells and inflammatory cells in autoimmune diseases.

F-FDG PET analysis in Takayasu arteritis
The first clinical study on TAK using 18

Aorta
In TAK, although PET can be used for diagnosis, PET/CT simplifies the identification of the lesion site. The reason is that PET helps obtain information in the longitudinal direction of the body, but its imaging ability in the horizontal plane of the body is less than desirable. In vasculitis, inflammation is often present in multiple blood vessels, and anatomically identifying the inflammation sites is important. CT provides additional information on the cross-section of the body, allowing for more a reliable and easier diagnostic method.
Because of the relatively large diameter of the ascending aorta, aortic arch, pulmonary artery, descending aorta, and abdominal aorta, the "ring sign" around the affected vessel wall is a typical finding of TAK and is highly reproducible ( Figure 1).
However, in arteriosclerotic plaques, such as vascular wall calcification, increased 18 F-FDG uptake may be observed if macrophages have been activated (12). Therefore, in the elderly patients with arteriosclerosis, caution is required in the diagnosis of vasculitis to avoid a false-positive result.

Primary branch arteries
The primary branches of the aorta, such as the common carotid, subclavian, brachiocephalic, and vertebral arteries, can be seen in the blood vessels without stenosis, indicating inflammation ( Figure 3). Such findings allow for therapeutic intervention before stenosis progression, which is clinically significant.

Blood vessel grafts
In cases of a primary branch stenosis progressing irreversibly in patients with significant ischemic symptoms,

Semi-quantitative evaluation using SUVmax
SUVmax is semi-quantitative marker presenting the degree of FDG uptake. SUVmax can be measured by placing the regions of interest at the sites of 18 F-FDG uptake in the vascular wall using the workstation software. However, since SUVmax measured using this method varies across facilities, they should be interpreted with caution.
Generally, SUVmax is significantly higher in patients with acute-phase TAK than in those with non-acute phase TAK (remission achieved) (11,15). For that reason, quantitative evaluation can be additionally used for diagnosis (15). At our facility, vascular SUVmax ranged from 2.1 to 5.3 in 45 patients with acute-phase TAK. However, the quantification should be performed carefully in order to avoid a false-positive 18 F-FDG uptake.

Assessment of disease activity by 18 F-FDG PET during treatment of TAK
The lack of disease-specific hematological markers inconvenience the diagnosis of TAK. Matrix metalloproteinase 3 is widely used as a marker for this disease, but it tends to increase after administration of steroids and may therefore not   be used as a reference in some cases (3,16). Therefore, to To verify whether 18 F-FDG uptake could be used as a quantitative marker, our group collected data on SUVmax and its target-to-background ratio (TBR) relevant to this disease, and we performed a statistical analysis. We defined the acute phase in accordance with the NIH guidelines (17) and found that SUVmax and CRP were elevated in acute-phase cases.
However, although the SUVmax values were also high in cases of relapse, the CRP levels were not so high. (Figures 5A and   B). In addition, the receiver operating characteristic curve analysis revealed that a cut-off SUVmax of 2. 1 strongly correlated with the disease state and that the diagnostic accuracy of quantitative values was actually high ( Figure 5C) (15). These results suggest that SUVmax and TBR reflect the disease state in patients with a suspected relapse during maintenance therapy and is therefore considered useful for therapeutic assessment.
However, the use of A 23-year-old woman with TAK was on corticosteroids 5 mg/day. ESR was 18 mm/h, but she had left arm pain with slight CRP elevation up to 1.1 mg/dL. 18 F-FDG PET/CT showed uptake in the left subclavian artery, and SUVmax was elevated (left). After increasing the prednisolone dose to 30 mg/day, the uptake disappeared, and SUVmax decreased (right). Strong 18 F-FDG uptake on her right side was due to an artificial graft, from the right axial artery to the right external iliac artery. therapeutic effect is yet to be insured under the Japanese health insurance system.

Conclusion
Evidence has been accumulated to support the use of 18

Sources of funding
None.  Figure 5A and B: Comparisons of CRP and SUVmax among patients who were untreated, relapsing on treatment, and stable on treatment for TAK All of the 39 patients with TAK were enrolled in this study. At first, the case were classified to active and inactive cases according to NIH score of TAK. Moreover, the active cases were divided into untreated and relapsing on treatment groups, and the inactive cases were defined as 'stable on treatment'. SUVmax in the two active groups were significantly higher than that in the stable on treatment group. CRP was statistically different among untreated, relapsing, and stable cases. SUVmax did not differ between untreated and relapsing cases. C: Comparisons of ROC curves between SUVmax, TBR, CRP, and ESR To detect active cases, AUCs in SUVmax (95.4%) and TBR (91.4%) were statistically superior to those in CRP (84.7%) and ESR (72.7%) (p<0.05).