State of the art of 18F-FDG PET/CT application in inflammation and infection: a guide for image acquisition and interpretation.

AIM: The diagnosis, severity and extent of a sterile inflammation or a septic infection could be challenging since there is not one single test able to achieve an accurate diagnosis. The clinical use of 18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) imaging in the assessment of inflammation and infection is increasing worldwide. The purpose of this paper is to achieve an Italian consensus document on [18F]FDG PET/CT or PET/MRI in inflammatory and infectious diseases, such as osteomyelitis (OM), prosthetic joint infections (PJI), infective endocarditis (IE), prosthetic valve endocarditis (PVE), cardiac implantable electronic device infections (CIEDI), systemic and cardiac sarcoidosis (SS/CS), diabetic foot (DF), fungal infections (FI), tuberculosis (TBC), fever and inflammation of unknown origin (FUO/IUO), pediatric infections (PI), inflammatory bowel diseases (IBD), spine infections (SI), vascular graft infections (VGI), large vessel vasculitis (LVV), retroperitoneal fibrosis (RF) and COVID-19 infections. METHODS: In September 2020, the inflammatory and infectious diseases focus group (IIFG) of the Italian Association of Nuclear Medicine (AIMN) proposed to realize a procedural paper about the clinical applications of [18F]FDG PET/CT or PET/MRI in inflammatory and infectious diseases. The project was carried out thanks to the collaboration of 13 Italian nuclear medicine centers, with a consolidate experience in this field. With the endorsement of AIMN, IIFG contacted each center, and the pediatric diseases focus group (PDFC). IIFG provided for each team involved, a draft with essential information regarding the execution of [18F]FDG PET/CT or PET/MRI scan (i.e., indications, patient preparation, standard or specific acquisition modalities, interpretation criteria, reporting methods, pitfalls and artifacts), by limiting the literature research to the last 20 years. Moreover, some clinical cases were required from each center, to underline the teaching points. Time for the collection of each report was from October to December 2020. RESULTS: Overall, we summarized 291 scientific papers and guidelines published between 1998 and 2021. Papers were divided in several sub-topics and summarized in the following paragraphs: clinical indications, image interpretation criteria, future perspectivess and new trends (for each single disease), while patient preparation, image acquisition, possible pitfalls and reporting modalities were described afterwards. Moreover, a specific section was dedicated to pediatric and PET/MRI indications. A collection of images was described for each indication. CONCLUSIONS: Currently, [18F]FDG PET/CT in oncology is globally accepted and standardized in main diagnostic algorithms for neoplasms. In recent years, the ever-closer collaboration among different European associations has tried to overcome the absence of a standardization also in the field of inflammation and infections. The collaboration of several nuclear medicine centers with a long experience in this field, as well as among different AIMN focus groups represents a further attempt in this direction. We hope that this document will be the basis for a "common nuclear physicians' language" throughout all the country. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40336-021-00445-w.

18Fluoride-based molecular imaging of coronary atherosclerosis in HIV infected patients.

BACKGROUND AND AIMS: Molecular imaging with 18Fluorodeoxyglucose (FDG) and 18F-sodium-fluoride (NaF) captures arterial inflammation and micro-calcification and can reveal potentially unstable atherosclerotic plaques. METHODS: We performed FDG and NaF PET/CT imaging in two clinically similar cohorts of patients living with HIV (PLWH) with no symptomatic cardiovascular disease. The prevalence and intensity of coronary artery uptake of each tracer, measured as target-to-background ratio (TBR), were assessed in patients at low and high cardiovascular risk. RESULTS: Ninety-three PLWH were submitted to PET/CT imaging with FDG (N = 43) and NaF (N = 50); 42% were at low and 58% at high cardiovascular risk. The intensity of uptake and multivessel coronary artery uptake were significantly higher with NaF than FDG both in low and high-risk patients. When each 18F-tracer was tested in low and high-risk patients, an equal proportion of subjects showed no vessel, single and multivessel NaF uptake; the same was true for no and single vessel uptake of FDG (no multivessel FDG uptake was noted). Waist circumference, CRP, D-dimer, HIV duration and treatment with nucleoside reverse transcriptase inhibitors were associated with high NaF uptake in univariable analyses; D-dimer remained significant in multivariable analyses (OR = 1.05; p=0.02). There were no significant associations with FDG uptake. CONCLUSIONS: The prevalence of coronary artery uptake was higher with NaF compared to FDG both in high and low risk patients, hence microcalcification imaging may be a more sensitive tool to detect coronary atherosclerosis than inflammation imaging. However, the uptake of each 18Fluoride tracer was similar between low and high-risk subjects, and this underscores the discordance between clinical and imaging based risk assessment. Future investigation should address the prognostic significance of NaF coronary artery uptake.

Molecular Imaging of Vascular Calcification with 18F-Sodium-Fluoride in Patients Infected with Human Immunodeficiency Virus.

18F-Sodium Fluoride (NaF) accumulates in areas of active hydroxyapatite deposition and potentially unstable atherosclerotic plaques. We assessed the presence of atherosclerotic plaques in 50 adult patients with HIV (HIV+) who had undergone two cardiac computed tomography scans to measure coronary artery calcium (CAC) progression. CAC and its progression are predictive of an unfavorable prognosis. Tracer uptake was quantified in six arterial territories: aortic arch, innominate carotid artery, right and left internal carotid arteries, left coronary (anterior descending and circumflex) and right coronary artery. Thirty-one patients showed CAC progression and 19 did not. At least one territory with high NaF uptake was observed in 150 (50%) of 300 arterial territories. High NaF uptake was detected more often in non-calcified than calcified areas (68% vs. 32%), and in patients without than in those with prior CAC progression (68% vs. 32%). There was no correlation between clinical and demographic variables and NaF uptake. In clinically stable HIV+ patients, half of the arterial territories showed a high NaF uptake, often in the absence of macroscopic calcification. NaF uptake at one time point did not correlate with prior progression of CAC. Prospective studies will demonstrate the prognostic significance of high NaF uptake in HIV+ patients.

The prognostic role of end of treatment FDG-PET-CT in patients with diffuse large B cell lymphoma can be improved by considering it with absolute monocyte count at diagnosis.

It is well established that some patients with diffuse large B-cell lymphoma (DLBCL) and the negative end of treatment PET-CT (EOT-PET-CT) will relapse, while a proportion with positive uptake can still obtain long-term EFS. We reviewed data of 200 consecutive, previously untreated patients with DLBCL recorded in Italy and Israel between 2007 and 2015. We found that patients with negative EOT-PET-CT with AMC > 630/mmc have a 3-years EFS of 72%, compared to those with AMC ≤ 630/mmc that have an EFS of 84%. Furthermore, considering patients with positive EOT-PET-CT, those with AMC > 630/mmc have a 3-years EFS of 8%, while those with AMC ≤ 630/mmc have an EFS of 38%. Thus, it appears that combining the gold standard for response evaluation EOT-PET-CT with a simple and inexpensive parameter like AMC at diagnosis, further improves prognostication in DLBCL. Applying this simple method can be useful for all doctors working in lymphoma clinical practice.

The role of 68Ga-PSMA PET/CT scan in biochemical recurrence after primary treatment for prostate cancer: a systematic review of the literature.

INTRODUCTION: Recurrence after primary treatment of prostate cancer is one of the major challenges facing urologists. Biochemical recurrence is not rare and occurs in up to one third of the patients undergoing radical prostatectomy. Management of biochemical recurrence is tailored according to the site and the burden of recurrence. Therefore, developing an imaging technique to early detect recurrent lesions represents an urgent need. Positron emission tomography (PET) of 68Ga-labelled prostate-specific membrane antigen (68Ga-PSMA) is an emerging imaging modality that seems to be a promising tool with capability to localize recurrent prostate cancer. A systematic review of literature was done to evaluate the role of 68Ga-PSMA PET/CT scan in patients with recurrent prostate cancer after primary radical treatment. EVIDENCE ACQUISITION: A systematic and comprehensive review of literature was performed in September 2017 analyzing the MEDLINE and Cochrane Library following the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. The following key terms were used for the search "PSMA," "prostate-specific membrane antigen," "positron emission tomography," "PET," "recurrent," "prostate cancer," "prostate neoplasm," "prostate malignancy," and "68Ga." Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. EVIDENCE SYNTHESIS: Thirty-seven articles met our inclusion criteria and were included in the analysis of this systematic review. Of the 37 articles selected for analysis only four studies were prospective. The overall detection rate of 68Ga-PSMA PET scan ranged from 47% up to 96.6%. The main advantage of this imaging technique is its relatively high detection rates at low serum PSA levels below 0.5 ng/mL (ranging from 11.1% to 75%). Higher serum PSA level was strongly associated with increased positivity on 68Ga-PSMA PET scan. 68Ga-PSMA PET scan was found superior to conventional imaging techniques (CT and MRI) in this setting of patients and even it seems to outperform choline-based PET scan. This technique provided significant changes in the therapeutic management of 28.6-87.1% of patients. CONCLUSIONS: After biochemical recurrence, the primary goal is to locate the recurrent lesions' site. 68Ga-PSMA PET/CT seems to be effective in identifying recurrence localization also for very low levels of PSA (<0.5 ng/mL) thus permitting to choose the best therapeutic strategy as early as possible. However, data available cannot be considered exhaustive and prospective randomized trials are needed.

Hybrid imaging of musculoskeletal infections.

This review article highlights the role of radiological and nuclear medicine techniques in diagnosis of musculoskeletal infections with particular regard to hybrid imaging of osteomyelitis, prosthetic joint infections, sternal infections and spine infections. Authors conclude on the complementary role of the several techniques with indications for an appropriate diagnostic flow chart, in the light of the recent European Association of Nuclear Medicine guidelines on infection.

Adrenal incidentaloma in thalassemia: a case report and literature review.

In the last 30 years the development and widespread use of modern imaging techniques has caused a 20-time increase in the diagnosis of adrenal incidentaloma (AI). Among AIs myelolipoma (ML) is reported with a frequency up to 10%. In the literature 8 patients with adrenal masses in thalassaemia or chronic haemolytic anaemia have been reported: five cases were shown to have extramedullary haematopoiesis (EH) and 3 ML. We describe here a case of an adult male affected by beta thalassaemia intermedia and large bilateral lipomatous adrenal masses. The patient was referred to our ward at the age of 55 and underwent hormonal testing, MRI, and SPECT/CT scans. Adrenal masses were hormonally inactive, and fat-containing on MRI and CT scans. SPECT/CT examination with 99mTccolloid demonstrated the presence of marrow tissue. ML and EH are the only two tumours with marrow tissue among lipomatous adrenal masses. In our patient a brown nodular mass was resected and histologically classified as ML. In benign adrenal masses, radiological follow-up is indicated; in case of large bilateral masses adrenal function tests are suggested periodically in order to detect possible adrenal hypofunction.

Bronchoalveolar lavage in systemic sclerosis with lung involvement: role and correlations with functional, radiological and scintigraphic parameters.

To evaluate the role and the prognostic value of bronchoalveolar lavage (BAL) in scleroderma patients with interstitial lung disease. We reviewed the records of 79 patients with systemic sclerosis (SSc) who had dyspnea and pulmonary involvement and underwent BAL study. Sixty-two patients were prospectively followed up for 12-36 months and re-evaluated by pulmonary function tests (PFTs). Seventy-nine SSc patients were enrolled (71 F and 8 M), 55 with limited and 24 with a diffuse form; mean age 55 ± 13 years; mean disease duration 55.2 ± 59 months. All patients were ANA positive, of these 30 were anti-topoisomerase-1 positive (anti-Topo1) and 22 were anti-centromere positive (ACA). Thirty-one patients had alveolitis (39.2%) that was neutrophilic in 12 patients, eosinophilic in 3 and mixed (neutrophilic and eosinophilic) in 16 patients. Compared to patients without alveolitis, those with alveolitis had a significant reduction of carbon monoxide diffusing capacity (DLCO), forced vital capacity (FVC) and more elevated lung high-resolution computed tomography (HRCT) scores. Furthermore, alveolar clearance was significantly accelerated. No differences were found between patients with and without alveolitis regarding disease subsets (diffuse vs limited-SSc); a significant predominance of anti-Topo1 antibodies was found in the alveolitis group and of ACA antibodies in the non-alveolitis cohort. During the follow-up, (range: 12-36 months) 62 patients, 26 with and 36 without alveolitis were re-evaluated with PFTs. In the alveolitis group, 12 patients (46.1%) showed stable lung function parameters and 14 had worsened (53.8%). In this group, 20 patients (77%) received cyclophosphamide (CYC): 11 (55%) worsened (5 of them died of cardio-pulmonary complications) and 9 (45%) remained stable. Six patients could not be treated; of these 3 remained stable and 3 worsened. Among 36 patients with normal BAL, 11 (30.5%) showed stable lung function parameters, 13 improved (36.1%) and 12 worsened (33.3%); in this last group, 2 patients died of extra-pulmonary complications. Six patients, with progression of lung fibrosis, were treated with CYC: 3 of them improved and 3 remained stable. Our study revealed a trend toward a more severe course in the SSc patients with BAL alveolitis; probably the non-significant result is related to the low number of the examined subjects and to the selection criteria. However, BAL remains the only tool to exclude lung infections and, in our experience, a useful instrument to evaluate interstitial lung disease in SSc patients.

The role of conventional radiography and scintigraphy in the third millennium.

Imaging represents a cornerstone for diagnosing and monitoring rheumatic diseases. In the last few years, with the availability of highly effective therapies, demand for the technical performance of imaging has increased exponentially, leading to rapid development of new technologies such as magnetic resonance imaging (MRI) and ultrasound (US). In both clinical practice and clinical trials, there is a need for tools that are sensitive to change and to therapy response, which are able to depict inflammatory changes early, before irreversible joint damage has occurred. Despite these advances, conventional radiography (CR) and bone scintigraphy (BS), the two oldest imaging tests, continue to provide enormous diagnostic and prognostic help for the study of many musculoskeletal disorders. Furthermore, CR is an inexpensive, widely available and reproducible tool for evaluating and monitoring structural damage. This chapter focuses on the roles of CR and BS in rheumatological clinical practice, taking into account their performance in comparison with the newer imaging techniques.

Thrombocytosis in systemic lupus erythematosus: a possible clue to autosplenectomy?

OBJECTIVE: Thrombocytosis can be due to a myeloproliferative disorder or to a reactive or secondary process; among these are connective tissue disorders, in particular systemic lupus erythematosus (SLE). Besides being an expression of active disease, this unusual finding has also been described in SLE complicated by autosplenectomy. We evaluated the prevalence of thrombocytosis in a series of SLE patients and its relationship to functional asplenia. METHODS: Platelet count was evaluated in 465 consecutive Caucasian patients with SLE (387 women, 78 men, median age 54 yrs). Thrombocytosis was defined as platelet count > 400 x 10(9)/l in at least 3 blood samples. All patients with thrombocytosis underwent peripheral blood smears for erythrocyte abnormalities and instrumental spleen evaluation. RESULTS: Seventeen patients (3.7%) with thrombocytosis were observed. Peripheral blood smear showed Howell-Jolly bodies, spherocytes, and target cells in 3/17 patients (17.6%). In the same 3 patients, ultrasound and computed tomography failed to evidence the spleen, and liver-spleen scans showed absence of splenic uptake (a finding indicative of functional autosplenectomy). One satisfied criteria for antiphospholipid syndrome (APS), and the other 2 patients had positive IgG antiphospholipid antibodies (aPL) at medium titer. CONCLUSION: The sudden appearance and persistence of thrombocytosis or even the apparent reversal of thrombocytopenia in patients with SLE should raise suspicion of autosplenectomy, in particular if secondary APS or aPL is present.

Nuclear medicine imaging of bone infections.

The inflammation and infection of bone include a wide range of processes that can result in a reduction of function or in the complete inability of patients. Apart from the inflammation, infection is sustained by pyogenic microorganisms and results mostly in massive destruction of bones and joints. The treatment of osteomyelitis requires long and expensive medical therapies and, sometimes, surgical resection for debridement of necrotic bone or to consolidate or substitute the compromised bones and joints. Radiographs and bone cultures are the mainstays for the diagnosis but often are useless in the diagnosis of activity or relapse of infection in the lengthy management of these patients. Imaging with radiopharmaceuticals, computed tomography and magnetic resonance are also used to study secondary and chronic infections and their diffusion to soft or deep tissues. The diagnosis is quite easy in acute osteomyelitis of long bones when the structure of bone is still intact. But most cases of osteomyelitis are subacute or chronic at the onset or become chronic during their evolution because of the frequent resistance to antibiotics. In chronic osteomyelitis the structure of bones is altered by fractures, surgical interventions and as a result of bone reabsorption produced by the infection. Metallic implants and prostheses produce artefacts both in computed tomography and magnetic resonance images, and radionuclide studies should be essential in these cases. Vertebral osteomyelitis is a specific entity that can be correctly diagnosed by computed tomography or magnetic resonance imaging at the onset of symptoms but only with radionuclide imaging is it possible to assess the activity of the disease after surgical stabilization or medical therapy. The lack of comparative studies showing the accuracy of each radiopharmaceutical for the study of bone infection does not allow the best nuclear medicine techniques to be chosen in an evidence-based manner. To this end we performed a meta-analysis of peer reviewed articles published between 1984 and 2004 describing the use of nuclear medicine imaging for the study of the most frequent causes of bone infections, including prosthetic joint, peripheric post-traumatic bone infections, vertebral and sternal infections. Guidelines for the choice of the optimal radiopharmaceuticals to be used in each clinical condition and for different aims is provided.

Osteomyelitis: clinical update for practical guidelines.

Bone infections represent a diagnostic or therapeutic challenge for the infectivologist, orthopaedic surgeon, radiologist and nuclear medicine physician. Staphylococcus aureus is the major bacterium responsible for bone infections although Mycobacterium tuberculosis is emerging as an infectious agent in Italy because of immigration from Africa and Asia. Osteomyelitis requires long and expensive antibiotic treatment, including rifampicin administered parenterally for several weeks and the use of antimicrobial-impregnated cement in prosthesis substitution. Sometimes it is necessary to carry out surgical debridement of a necrotic bone or the consolidation of compromised bones and joint prosthesis implants. Radiographs and bone cultures are mainstays for the diagnosis of bone infections but are often useless in the lengthy management of these patients. Diagnosis of skeletal infections still includes conventional radiography but magnetic resonance imaging is essential in haematogenous and spinal infections. Bone scans are still useful in acute osteomyelitis whereas scintigraphy using labelled white blood cells is preferred in infections of peripheral bone segments or joint prosthesis. In the axial skeleton a combination of an agent for detecting inflammation ((67)Ga citrate) and a metabolic agent ((99m)Tc-methylene diphosphonate) enables an infection and an area of increased metabolic activity to be distinguished. [(18)F]Fluorodeoxyglucose positron emission tomography, where available, has a significant impact in the study of infections using radionuclides: high-resolution tomographic images represent an effective alternative to gallium in the assessment of inflammation of spine lesions but a comparison with morphological examinations (computed tomography or magnetic resonance imaging) is essential.

Scintigraphy in rheumatic diseases.

The aim of this review is to summarise the clinical role of nuclear medicine in rheumatology taking into consideration the most specific diagnostic applications and other worthwhile therapeutic contributions. Traditional bone scintigraphy and recent inflammation-targeting radiopharmaceuticals, such as radiolabelled leucocytes and immunoscintigraphy, now allow us to obtain highly sensitive total-body and tomographical imaging information that can be used for the diagnosis of osteoarticular disease. The most common extra-articular manifestations of rheumatic diseases due to digestive, central nervous, respiratory and cardiovascular system involvement can be diagnosed by specific scintigraphic methods. Radiosynovectomy plays an important role in providing effective treatment for some joint diseases that are resistant to pharmacological therapy. Diagnostic and therapeutic applications of nuclear medicine show the highest efficacy in the early phase of rheumatic diseases. In more advanced stages, scintigraphical techniques play a complementary role to radiographical investigations in the assessment of prognosis and therapy efficacy.

Autosplenectomy and antiphospholipid antibodies in systemic lupus erythematosus: A pathogenetic relationship?

OBJECTIVES: To describe a systemic lupus erythematosus (SLE) patient with functional asplenia and antiphospholipid syndrome (APS) and to review the literature to better define its pathogenesis and diagnosis, emphasizing a possible relationship with antiphospholipid antibodies (aPL). METHODS: Descriptive report of 1 case and review of the literature by means of a MEDLINE search from 1966 to 2002. RESULTS: A SLE patient presented with cutaneous vasculitis and an unexpected thrombocytosis which resulted from autosplenectomy. Subsequently, she developed full-blown APS. In the literature, autosplenectomy has been described only in 1 other case of APS secondary to SLE. However, clinical or laboratory features linked to aPL occurred in several other cases among the 17 cases reported with functional asplenia. CONCLUSIONS: Autosplenectomy in SLE may be pathogenetically related to aPL. Thrombocytosis, unusual in SLE, may be a diagnostic clue of this condition. Pneumococcal vaccination is warranted to prevent life-threatening infections that frequently complicate this asplenia.