Positron Emission Tomography / Computed Tomography (PET/CT) - Medical Science Assignment Help

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1/Comparison of histopathology and preoperative 18F-FDG-PET/CT of osteomyelitis aiming for image guided surgery: A preliminary trial
Positron emission tomography / computed tomography (PET/CT) using the glucometabolic tracer 2-deoxy-2-[18F] fluoro-D-glucose (18F-FDG) is widely used to diagnose malignant tumors and detect distant metastasis. Accumulation of FDG is nonspecific, and it is well-known that it can indicate inflammatory cells and sites of in- flammation [8], and its effectiveness in detecting osteomyelitis has been reported recently [9].
Takaki, M., Takenaka, N., Mori, K., Harada, S., Asahara, T., Katoh, N., ... & Matsushita, T. (2020). Comparison of histopathology and preoperative 18F-FDG-PET/CT of osteomyelitis aiming for image guided surgery: A preliminary trial. Injury, 51(4), 871-877.
(Takaki et al., 2020)

2/Multiagent imaging of inflammation and infection with radionuclides
Prototypical molecular imaging tests use agents such as gallium-68 citrate, labeled leukocytes and fluorine-18 fluorodeoxyglucose ([18F]FDG). These agents, which reflect the physiological changes that are part of the inflammatory process, are taken up directly by cells, tissues and organs, or are attached to native substances that sub- sequently migrate to an inflammatory focus.
In general, positron emission tomography (PET) offers several advantages over SPECT imaging. PET provides three-dimensional images of the whole body with superior resolution and facilitates [especially, when combined with CT (PET/CT)] precise localization of abnormal uptake. Furthermore, semiquantitative analysis is more readily available and could be helpful for differentiating between infections and other causes of uptake,
[18F]FDG, a well-established tool in oncology, has been an increasing focus of attention in the field of infection and inflammation imaging over the past decade, since [18F]FDG also accumulates in activated leukocytes, which use glucose as an energy source only after activation during their metabolic burst [31]. Transport of [18F]FDG across the cell membrane is mediated by glucose transporter proteins (GLUT). Intracellular [18F]FDG is phosphorylated by the enzyme hexokinase and trapped in the cell. With the exception of a few organs, physiological uptake of [18F]FDG is low and clearance from non-target tissue is rapid, resulting in relatively high target-to-background ratios. With the new hybrid PET/CT systems, diagnostic evaluation can be completed in a single visit in just 1–2 h (including the waiting time, after injection, necessary for sufficient tracer uptake). Compared with many other radiopharmaceuticals, [18F]FDG has a very favorable dosimetry. It is very sensitive and in most situations has a high negative predictive value. There are, however, limi- tations to this agent, notably its specificity. [18F]FDG PET merely detects enhanced glucose metabolism and is therefore unable to discriminate reliably between infection/ inflammation, malignancy and any other hypermetabolic state. [18F]FDG also cannot distinguish between different inflammatory pathways, which can be relevant in some clinical situations [31].

Combined EANM/SNMMI guidelines for the use of [18F]FDG in infection and inflammation have been pub- lished. Major indications are peripheral bone osteomyelitis (non-postoperative, non-diabetic foot) (Fig. 5), sarcoidosis (Fig. 6), suspected spinal infection (Fig. 7), evaluation of fever of unknown origin (FUO),
The imaging characteristics of the positron emitter gallium- 68 (68Ga) are superior to those of 67Ga by virtue of the higher spatial resolution and quantitative features of PET in comparison with single-photon imaging. 68Ga-citrate has suitable radiophysical and radiopharmaceutical properties: high positron yield and a half-life of 68 min, and thus, showing rapid blood clearance, quick diffusion and target localization, is able to match the pharmacokinetics of many peptides and other small molecules [61]. In addition, this agent can be generator produced, and several generators are commercially available.
Palestro, C. J., Glaudemans, A. W., & Dierckx, R. A. (2013). Multiagent imaging of inflammation and infection with radionuclides. Clinical and translational imaging, 1(6), 385-396.
(Palestro, Glaudemans, & Dierckx, 2013)
(Palestro et al., 2013)

3/Can Sequential 18F-FDG PET/CT Replace WBC Imaging in the Diabetic Foot?
Another possibility is the use 18F-FDG PET/CT, which has some theoretic advantages: no blood manipulation is necessary, acquisition time is shorter, and image resolution is higher. 18F-FDG accumulates in inflammatory cells be- cause these, like malignant cells, metabolize glucose as a source of energy (16). With the routine 18F-FDG PET pro- tocols, it is not possible to reliably distinguish infection from inflammation.
Familiari, D., Glaudemans, A. W., Vitale, V., Prosperi, D., Bagni, O., Lenza, A., ... & Signore, A. (2011). Can sequential 18F-FDG PET/CT replace WBC imaging in the diabetic foot?. Journal of Nuclear Medicine, 52(7), 1012-1019.
(Familiari et al., 2011)

4/18F-FDG PET/CT in the diagnosis of occult bacterial infections in children
8F-FDG PET/CT scan has the ability to screen the whole body for functional activity of inflammation, has high spatial and contrast resolution, and yields results within a very short period of time. Owing to these reasons, it is increasingly used in the diagnostic work- up of infectious diseases [2]. The main indications for 18F- FDG PET/CT in adult patients with suspected infection are: FUO, chronic osteomyelitis, vertebral osteomyelitis,
Del Rosal, T., Goycochea, W. A., Méndez-Echevarría, A., de Villalta, M. G. F., Baquero-Artigao, F., Coronado, M., ... & Albajara, L. (2013). 18 F-FDG PET/CT in the diagnosis of occult bacterial infections in children. European journal of pediatrics, 172(8), 1111-1115.
(Del Rosal et al., 2013)

5/18F-Fluorodeoxyglucose positron emission tomography and infectious diseases: current applications and future perspectives
such techniques are affected by a substantial lack of sensitivity particularly in hematopoietic structures [2,3]. Moreover, the planar imaging may affect precise localization and they are usually expensive and time consuming. Techniques based on evaluation of glucose metabolism (FDG-uptake), like PET/CT and more recently PET/MRI, have overcome those limitations, increasing the use of nuclear imaging in the setting of infectious diseases.
Although acute osteomyelitis usually does not represent a diagnostic challenge by putting together local signs of inflammation (i.e., reduced motion, pain, and tenderness of the involved bone) with conventional imaging findings, accurate diagnosis of chronic osteomyelitis is often difficult [63]. Chronic osteomyelitis is a severe orthopedic com- plication which may be extremely difficult to diag- nose and treat, particularly in presence of pre-existing alterations because of previous trauma or surgery.
Compared with conventional imaging or other nuclear medicine modalities, FDG-PET has shown a robust sensitivity and specificity reaching 96 and 91%, respectively, in a published meta- analysis [64]
In complicated diabetic foot, FDG-PET/CT has been demonstrated not only to be highly sensitive in excluding osteomyelitis but also highly specific in differentiation from Charcot neuropathy compared with MRI that often shows misleading findings caused by soft tissue edema
Monitoring of treatment response currently represents the most promising application of FDG-PET/CT in the setting of infectious diseases . Establishing optimal treatment duration is of great value considering potential drug toxicity, resistance selection, and healthcare costs related to prolonged antibiotic therapies. While evaluating infective lesions, FDG-PET analysis is often based on visual-normalized interpretation with only a few reports analyzing a quantitative approach and a substantial lack of standardized methods [87
However, it remains to be determined how quantitative changes in FDG-uptake are associated with improved clinical outcomes as well as the clinical relevance of persist- ent residual FDG-uptake after effective treatment
Moreover,
The data presented in this review clearly demon- strate how FDG-PET/CT will increasingly play a major role in the assessment of patients affected by a wide range of infectious diseases like osteo- myelitis, infected prostheses, endocarditis, and even lung and CNS infections. FDG-PET has proven to be an excellent imaging modality not only for the diagnosis, but also for the staging and evaluation of treatment response overcoming many limitations associated with structural imaging techniques or conventional scintigraphic methodologies. The ability of FDG-PET to quantify disease activity seems particularly attractive, providing the possibility to avoid invasive diagnostic tests, to identify multi- focal infection and to monitor early response to antibiotic treatment. At this juncture, FDG-PET should be used to improve the clinical management of infectious disorders although further validation with prospective randomized/controlled studies is strongly encouraged.
Bassetti, M., Carnelutti, A., Muser, D., Righi, E., Petrosillo, N., Di Gregorio, F., ... & Alavi, A. (2017). 18F-Fluorodeoxyglucose positron emission tomography and infectious diseases: current applications and future perspectives. Current opinion in infectious diseases, 30(2), 192-200.
(Bassetti et al., 2017)

6/Accuracy of diagnostic imaging modalities for peripheral post-traumatic osteomyelitis – a systematic reviewof the recent literature
osteomyelitis, also known as ‘fracture- related’ osteomyelitis, is a feared complication for its difficult recognition, significant treatment duration and high recurrence rate. Infection can present acutely in the first few weeks after internal fixation, in a delayed manner with low-grade infection or late with infected non-union or persistent infection after frac- ture healing [1–3].
Early treatment of an acute infection can prevent progression to established osteomyelitis but this condition still affects 2–4% of all patients undergoing an open reduction and internal fixation of an open or closed fracture [7].
The key for a successful treatment of osteomyelitis is a prompt and accurate diagnosis. However, this diagnostic process in particular is challenging [7–19]. Many imaging modalities such as magnet- ic imaging resonance (MRI), three-phase bone scintigraphy (TPBS), white blood cell (WBC) scintigraphy, antigranulocyte antibody (AGA) scintigraphy, fluorodeoxyglucose positron emission tomography (FDG-PET) and plain computed tomography (CT) are frequently used for diagnosing or excluding this condition.

In the past 10 years, there has been a huge development in new camera systems, combining nuclear medicine techniques such as single-photon emission computed tomography (SPECT) and PET with radiological techniques such as CT and MRI. Although these hybrid camera systems (SPECT-CT, PET- CT or PET-MRI) may lead to better localisation of the infection and, as a consequence, to better diagnostic accuracy rates, their diagnostic value for osteomyelitis has not yet been established [19–21].
Choosing the most appropriate imaging technique for osteomyelitis remains difficult because there are advantages, disadvantages, pitfalls and contraindications of each option within the field of both nuclear medicine and clinical radiology. First of all, osteomyelitis is a condition that occurs in a very heterogeneous patient population. Limited mobility of the patient might not allow dual time point imaging and location of the infection, and co- morbidities and metal implants may affect the accuracy of the imaging techniques used.
FDG-PET is a relatively quicker whole-body imaging procedure (one imaging time point 60 minutes after injection) that can be used to detect multiple foci throughout the body. Disadvantages are that recent fractures and the presence of metallic hardware may decrease the accuracy of FDG-PET since FDG uptake will also be increased in inflammatory re- actions [59].
Govaert, G. A., IJpma, F. F., McNally, M., McNally, E., Reininga, I. H., & Glaudemans, A. W. (2017). Accuracy of diagnostic imaging modalities for peripheral post-traumatic osteomyelitis–a systematic review of the recent literature. European journal of nuclear medicine and molecular imaging, 44(8), 1393-1407.
(Govaert et al., 2017)

7/Evaluation of Dynamic [18F]-FDG-PET Imaging for the Detection of Acute Post-Surgical Bone Infection
Osteomyelitis is a complicated infection that often requires surgical debridement as well as appropriate, long-term antimicrobial therapy This is particularly true in chronic infections [1], which are characterized by a compromised blood supply and the formation of necrotic bone [2,3]. Thus, the definitive detection of infection in its early, acute phase would be ideal.
Positron emission tomography utilizing 2-deoxy-2-[18F]-fluor- odeoxyglucose (FDG-PET) has also been investigated as an imaging modality for the diagnosis of osteomyelitis in the post- operative setting [7–10]. Some studies have concluded that FDG- PET could be used to differentiate recuperative remodeling from infection as early as 14–21 days post-surgery [8–10]. While these results are promising, the transition to a chronic state can occur in as few as 10 days post-infection [3]. This suggests that FDG-PET as it is generally applied in the clinical setting provides definitive diagnostic results only as the infection nears or progresses into the chronic stage.
Because glucose consumption is increased in metabolically active cells, the uptake of FDG as a glucose analog is increased in rapidly dividing tumor cells and activated inflammatory cells.
Brown, T. L., Spencer, H. J., Beenken, K. E., Alpe, T. L., Bartel, T. B., Bellamy, W., ... & Smeltzer, M. S. (2012). Evaluation of dynamic [18 F]-FDG-PET imaging for the detection of acute post-surgical bone infection. PLoS One, 7(7), e41863.
(Brown et al., 2012)

8/FDG PET/CT imaging in the diagnosis of osteomyelitis in the diabetic foot
Radiological changes may appear later in the course of the disease, with a time lag of up to 2 weeks [4, 5]. In addition, bone structure changes seen on CT images may be have a number of different causes. Bone biopsy, the definitive test for the diagnosis of osteomyelitis, cannot always be performed, particularly in patients with vascular problems, and its reliability may be reduced by contamination of biopsy samples by cutaneous microorganisms [6]. Therefore, physicians frequently rely on imaging tests for correct diagnosis. Nuclear medicine plays an important role in the evaluation of osteomyelitis
18F-FDG, a nonspecific indicator of increased intracellular glucose metabolism, accumulates in sites of active malignancy as well as in infectious and inflammatory processes [8–11]. Hybrid PET/CT imaging allows simultaneous metabolic and structural assessment of regions in which the presence of a malignant or infectious process is suspected. In a single imag- ing session the presence of a hypermetabolic site of disease can be confirmed and precisely localized to specific anatomical structures.
Patients were instructed to fast, except for glucose-free oral hydration, for 4–6 h before injection of 185–555 MBq (5–15 mCi) of 18F-FDG and to keep their regular drug schedule. Blood glucose levels were measured before administration of radiotracer.
Any site of focal or diffuse increased FDG uptake detected on the PET component of the PET/CT study as compared to the physiological tracer activity in adjacent structures was defined as an infectious process.
The presence of focal FDG uptake and its localization to bone were the diagnostic criteria for osteomyelitis on FDG PET/CT regardless of the presence or absence on CT. There- fore, a site of focal increased FDG uptake in bone was defined as true-positive (TP) if confirmed as osteomyelitis and false-positive (FP) if there was no further evidence of bone infection. Absence of abnormal FDG uptake, increased activity located only in soft tissues, or diffuse, mildly increased uptake in adjacent bones were defined as true-negative (TN) if there was no further evidence of osteomyelitis and false- negative (FN) if bone infection was further diagnosed.
Bone and radiolabelled white blood cell scintigraphy are commonly used for the diagnosis of osteomyelitis. Bone scintigraphy is highly sensitive but has a lower specificity due to false-positive FP studies in the presence of coexisting pathologies such as neuroarthropathy, trauma or cellulitis [16]. Labelling of white blood cells requires handling of blood and is a time- consuming and technically demanding procedure.
FDG imaging has the advantages of shorter study time and of high-quality tomographic images and has been vali- dated as a highly sensitive modality for detecting infectious foci [17–19].
Kagna, O., Srour, S., Melamed, E., Militianu, D., & Keidar, Z. (2012). FDG PET/CT imaging in the diagnosis of osteomyelitis in the diabetic foot. European journal of nuclear medicine and molecular imaging, 39(10), 1545-1550.
(Kagna, Srour, Melamed, Militianu, & Keidar, 2012)
(Kagna et al., 2012)

9/Kinetic Modelling of [68Ga]Ga-DOTA-Siglec-9 in Porcine Osteomyelitis and Soft Tissue Infections
. However, while the isotopes 111In and 99mTc are suitable for gamma camera imaging, they cannot be used for PET imaging. This is a technical disadvantage, as the counting efficiency is typically an order of magnitude higher for the PET scanner than for the gamma camera, and the spatial resolution is superior.
These delays are acceptable with 111In (T1 = 2.8 days) and 99mTc (T1 = 6 h), 22
but in relation to PET imaging, the shorter physical half-lives of the two most widely used isotopes,
18F (T1 = 110 min) and 68Ga (T1 = 68 min), make long uptake times problematic.
Such a tracer would potentially enable faster imaging, and at the same time, the handling of blood products from the patient would be avoided.
A relevant target molecule is vascular adhesion protein 1 (VAP-1), currently known as a primary amine oxidase (AOC3, EC 1.4.3.21), which is acting both as an adhesion molecule and as a regulatory enzyme in the process of leukocyte binding to the endothelium of blood vessels in infected and inflamed tissue [5,6]. Under normal conditions, VAP-1 is stored in intracellular granules. Upon an inflammatory stimulus, VAP-1 is rapidly translocated to the endothelial cell surface, where it is readily accessible to intravenously administered PET ligands. As reviewed in [7], 68Ga-labelled synthetic peptides that bind to VAP-1 have been investigated in different experimental infection and inflammation models, and some have shown a better distinction than [18F]FDG between cancer and inflammation. Overall, the review considers VAP-1 to be an optimal target for imaging of inflammation.
It may be noted that VAP-1 imaging will not distinguish between infection and inflammation, but because VAP-1 is involved in leukocyte extravasation, it is directly linked to the body’s natural response to infection. Imaging of VAP-1 expression may even be used to study this process, especially if the kinetics of the VAP-1 imaging tracer are known.
Jødal, L., Roivainen, A., Oikonen, V., Jalkanen, S., Hansen, S. B., Afzelius, P., ... & Jensen, S. B. (2019). Kinetic modelling of [68Ga] Ga-DOTA-Siglec-9 in porcine osteomyelitis and soft tissue infections. Molecules, 24(22), 4094.
(Jødal et al., 2019)

10/Three cases of fever of unknown origin (FUO) with acute multifocal non-bacterial osteitis (NBO) as reactive osteomyelitis
Fever of unknown origin (FUO) has a variety of etiologies. Despite advances in technology for diagnosis, a consider- able number of cases remain unclear. Osteomyelitis is an inflammation of bone caused by infecting organisms, which is a classic cause of FUO.
Osteomyelitis is defined as an inflammation of bone caused by an infecting organism. The metaphyseal segment of long bones are the preferred sites of acute hematogenous osteomyelitis and primary acute osteomyelitis of the epiphysis, unlike that of the metaphysis, which is rare when the secondary ossification center forms to create the physis, a mechanical barrier to infection. Osteomyelitis can be classified as acute, subacute, or chronic depending on the duration of symptoms, as exogenous or hematogenous based on the mechanism of infection, and also as pyogenic or non-pyogenic based on the host response to the disease.
The histology of acute suppurative osteomyelitis demonstrates devitalized lamellar bone with scalloped edges, absence of stainable osteocytes and osteoblasts, edema, and granulocytic infiltration of surrounding tissues. The histology of chronic osteomyelitis shows irregular fragments of devitalized bone surrounded by dense fibrous tissue with infiltrations of plasma cells and lymphocytes, but only a few granulocytes. Sclerosing osteomyelitis is a chronic form of disease in which the bone is thickened and dis- tended; however, abscesses and sequestra are absent [2].
Hong, Y. H. (2013). Three cases of fever of unknown origin (FUO) with acute multifocal non-bacterial osteitis (NBO) as reactive osteomyelitis. Rheumatology international, 33(1), 253-257.
(Hong, 2013)

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