The Role of Fibroblast Activation Protein Inhibitor Positron Emission Tomography in Inflammatory and Infectious Diseases: An Updated Systematic Review.

The role of fibroblast activation protein inhibitor (FAPI) positron emission tomography/computed tomography (PET/CT) is emerging for the assessment of non-oncological diseases, such as inflammatory and infectious diseases, even if the evidence in the literature is still in its initial phases. We conducted a systematic search of Scopus, PubMed/MEDLINE, Embase, and Cochrane library databases for studies published before 31 December 2023 reporting infectious and inflammatory disease imaging with FAPI PET/CT. We included twenty-one studies for a total of 1046 patients. The most frequent disease studied was lung interstitial disease, investigated in six studies for a total of 200 patients, followed by bone and joint diseases in two studies and 185 patients, IgG4-related disease in 53 patients, and Crohn's disease in 30 patients. Despite the heterogeneity of studies in terms of study design and technical features, FAPI PET/CT showed a high detection rate and diagnostic role. Moreover, when compared with 2-[18F]FDG PET/CT (n = 7 studies), FAPI PET/CT seems to have better diagnostic performances. The presence of chronic inflammation and tissue remodeling, typical of immune-mediated inflammatory conditions, may be the underlying mechanism of FAPI uptake.

EANM consensus document on the use of [18F]FDG PET/CT in fever and inflammation of unknown origin.

PURPOSE: Patients with fever and inflammation of unknown origin (FUO/IUO) are clinically challenging due to variable clinical presentations with nonspecific symptoms and many differential diagnoses. Positron emission tomography/computed tomography (PET/CT) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is increasingly used in FUO and IUO, but the optimal diagnostic strategy remains controversial. This consensus document aims to assist clinicians and nuclear medicine specialists in the appropriate use of [18F]FDG-PET/CT in FUO and IUO based on current evidence. METHODS: A working group created by the EANM infection and inflammation committee performed a systematic literature search based on PICOs with "patients with FUO/IUO" as population, "[18F]FDG-PET/CT" as intervention, and several outcomes including pre-scan characteristics, scan protocol, diagnostic yield, impact on management, prognosis, and cost-effectiveness. RESULTS: We included 68 articles published from 2001 to 2023: 9 systematic reviews, 49 original papers on general adult populations, and 10 original papers on specific populations. All papers were analysed and included in the evidence-based recommendations. CONCLUSION: FUO and IUO remains a clinical challenge and [18F]FDG PET/CT has a definite role in the diagnostic pathway with an overall diagnostic yield or helpfulness in 50-60% of patients. A positive scan is often contributory by directly guiding treatment or subsequent diagnostic procedure. However, a negative scan may be equally important by excluding focal disease and predicting a favorable prognosis. Similar results are obtained in specific populations such as ICU-patients, children and HIV-patients.

Dual-Time-Point 18F-FDG PET/CT in Infective Endocarditis: Impact of Delayed Imaging in the Definitive Diagnosis of Endocarditis.

Infective endocarditis (IE) is a major public health condition due to the associated high morbidity and mortality. Our objective was to evaluate the utility of dual-time 2-deoxy-2-[18F] fluoro-D-glucose (18F-FDG) Positron Emission Tomography/Computed Tomography (PET/CT) imaging in the diagnosis of active IE in patients with suspected native valve endocarditis (NVE) and prosthetic valve endocarditis (PVE). For this purpose, a retrospective study was carried out, including patients suspicious of NVE or PVE who underwent a dual-time-point 18F-FDG PET/CT. A final diagnosis was established by the Endocarditis Team after patient follow-up using all the available findings. Sixty-nine patients were assessed. A final diagnosis of NVE was established in 3 patients of the 34 by 18F-FDG PET/CT and in the case of PVE was established in 20 patients of the 35. A statistically significant association was found when evaluating the association between PET diagnosis at early acquisition and final diagnosis of IE (χ2 = 30.198, p < 0.001) and PET diagnosis at delayed acquisition for final diagnosis of IE (χ2 = 9.412, p = 0.002). Delayed PET/CT imaging determined the IE diagnosis in 16/58 of the studies. In conclusion, delayed 18F-FDG PET/CT imaging seems to be useful in improving the definitive diagnosis of IE.

Diagnostic imaging of the diabetic foot: an EANM evidence-based guidance.

PURPOSE: Consensus on the choice of the most accurate imaging strategy in diabetic foot infective and non-infective complications is still lacking. This document provides evidence-based recommendations, aiming at defining which imaging modality should be preferred in different clinical settings. METHODS: This working group includes 8 nuclear medicine physicians appointed by the European Association of Nuclear Medicine (EANM), 3 radiologists and 3 clinicians (one diabetologist, one podiatrist and one infectious diseases specialist) selected for their expertise in diabetic foot. The latter members formulated some clinical questions that are not completely covered by current guidelines. These questions were converted into statements and addressed through a systematic analysis of available literature by using the PICO (Population/Problem-Intervention/Indicator-Comparator-Outcome) strategy. Each consensus statement was scored for level of evidence and for recommendation grade, according to the Oxford Centre for Evidence-Based Medicine (OCEBM) criteria. RESULTS: Nine clinical questions were formulated by clinicians and used to provide 7 evidence-based recommendations: (1) A patient with a positive probe-to-bone test, positive plain X-rays and elevated ESR should be treated for presumptive osteomyelitis (OM). (2) Advanced imaging with MRI and WBC scintigraphy, or [18F]FDG PET/CT, should be considered when it is needed to better evaluate the location, extent or severity of the infection, in order to plan more tailored treatment. (3) In a patient with suspected OM, positive PTB test but negative plain X-rays, advanced imaging with MRI or WBC scintigraphy + SPECT/CT, or with [18F]FDG PET/CT, is needed to accurately assess the extent of the infection. (4) There are no evidence-based data to definitively prefer one imaging modality over the others for detecting OM or STI in fore- mid- and hind-foot. MRI is generally the first advanced imaging modality to be performed. In case of equivocal results, radiolabelled WBC imaging or [18F]FDG PET/CT should be used to detect OM or STI. (5) MRI is the method of choice for diagnosing or excluding Charcot neuro-osteoarthropathy; [18F]FDG PET/CT can be used as an alternative. (6) If assessing whether a patient with a Charcot foot has a superimposed infection, however, WBC scintigraphy may be more accurate than [18F]FDG PET/CT in differentiating OM from Charcot arthropathy. (7) Whenever possible, microbiological or histological assessment should be performed to confirm the diagnosis. (8) Consider appealing to an additional imaging modality in a patient with persisting clinical suspicion of infection, but negative imaging. CONCLUSION: These practical recommendations highlight, and should assist clinicians in understanding, the role of imaging in the diagnostic workup of diabetic foot complications.

Brain Nocardiosis Defined by 18 F-Fluorocholine PET/CT.

ABSTRACT: Nocardia infection (nocardiosis) is usually acquired by inhalation; so pulmonary nocardiosis is the most common clinical presentation. Extrapulmonary localization occurs through hematogenous dissemination or contiguous spread. Nocardia can involve the central nervous system in a very reduced number of patients, mainly in immunocompromised. We present a case of a 56-year-old woman with a history of aggressive systemic mastocytosis, treated with chemotherapy 1 year ago. Patient reported intense headache, disorientation, and blurry vision without other symptoms being diagnosed with a rare brain nocardiosis by Nocardia cerradoensis . Neither bacteremia nor pulmonary involvement was detected. Brain PET/CT illustrated 18 F-fluorocholine avidity on brain abscesses.

Molecular Imaging in Inflammatory Bowel Disease.

Inflammatory bowel diseases (IBD) are chronic immune-mediated inflammatory diseases affecting the gastrointestinal tract. Classically, two subtypes of IBD are recognized: Ulcerative colitis and Crohn's disease. There is not a single and reliable test for IBD diagnosis but the nuclear medicine techniques like 99mTc-HMPAO autologous labelled leukocytes scintigraphy (WBCS) and PET/CT plays a role in the management of IBD. Leukocytes can be labelled "in vitro" (using 99mTc-HMPAO in Europe or 111In-oxine in America) or "in vivo" using antigranulocyte monoclonal antibodies. Nuclear medicine techniques are not the first choice to investigate IBD. Ultrasonography and magnetic resonance (radiation free) are probably the first option, and the diagnosis is commonly established by endoscopic biopsies. Nevertheless, WBCS is highly sensitive and accurate and represent a real option when other methods cannot used for whatever reason. In fact, a normal scan discards the presence of active IBD. The test is also useful to measure the extension and severity of the diseases and to evaluate the response to treatment. PET/CT imaging using 18F-FDG has recently been introduced and studied in both children and adults showing an excellent sensitivity for detecting active intestinal inflammation, but poor specificity in some studies. PET alone appears to be sufficient for the evaluation of ulcerative colitis, but PET/CT provides considerably more information than PET alone in the evaluation of Crohn's disease. Current clinical applications of PET in IBD include its use in the early evaluation of IBD, especially in children who may not tolerate an invasive test such as colonoscopy. Many questions remain to be answered, but PET appears to be a promising tool in the non-invasive evaluation of IBD. On the other hand, PET/MR could become in the near future a powerful tool in the evaluation of IBD patients. In addition, immuno-PET with antibodies targeting innate immune markers is also being investigated to detect colonic inflammation. The development of these technologies in humans could offer a less invasive method than endoscopy for the diagnosis and monitoring of IBD.

A systematic review about the role of preoperative 18F-FDG PET/CT for prognosis and risk stratification in patients with endometrial cancer.

OBJECTIVE: To analyse the available literature on the prognostic value of preoperative 18F-FDG PET/CT metabolic parameters and their usefulness in risk stratification in patients with endometrial cancer (EC). MATERIAL AND METHODS: Pubmed searches used "(endometr* OR uter*) AND (PET OR FDG)" as keywords from January-2000 to June-2020. References in included articles were checked for possible publications not included in the first search. Studies evaluating the prognostic value of preoperative 18F-FDG PET/CT and its role for risk stratification in patients with EC were included. Non-original articles (reviews, editorials, letters, legal cases, interviews, case reports, etc.) were not included. RESULTS: Twenty-six studies (1918 patients) were selected according to the inclusion criteria in this review. Thirteen studies (939 patients) related to the prognostic role of preoperative 18F-FDG PET/CT and 14 studies (1036 patients) related to its role in risk stratification were included. Parameters such as SUVmax, metabolic tumour volume (MTV) and total lesion glycolysis (TLG) of the primary tumour were analysed. CONCLUSIONS: Preoperative SUVmax is useful for non-invasive diagnosis and for deciding the appropriate therapeutic strategy, as it could be used as an independent prognostic marker for recurrence and survival in EC. In addition, both preoperative VTM and GTL could be independent prognostic factors for predicting recurrence and survival, but there is still insufficient scientific evidence. The usefulness of SUVmax for risk stratification is limited (there is insufficient literature that 18F-FDG PET/CT can replace surgical staging), although VTM and GTL are more accurate and have a valuable role in risk stratification of EC. However, larger multicentre studies with adequate follow-up time are needed to confirm these findings.

A Head-to-Head Comparison of 18F-Fluorocholine PET/CT and Conventional MRI as Predictors of Outcome in IDH Wild-Type High-Grade Gliomas.

(1) Aim: To study the associations between imaging parameters derived from contrast-enhanced MRI (CE-MRI) and 18F-fluorocholine PET/CT and their performance as prognostic predictors in isocitrate dehydrogenase wild-type (IDH-wt) high-grade gliomas. (2) Methods: A prospective, multicenter study (FuMeGA: Functional and Metabolic Glioma Analysis) including patients with baseline CE-MRI and 18F-fluorocholine PET/CT and IDH wild-type high-grade gliomas. Clinical variables such as performance status, extent of surgery and adjuvant treatments (Stupp protocol vs others) were obtained and used to discriminate overall survival (OS) and progression-free survival (PFS) as end points. Multilesionality was assessed on the visual analysis of PET/CT and CE-MRI images. After tumor segmentation, standardized uptake value (SUV)-based variables for PET/CT and volume-based and geometrical variables for PET/CT and CE-MRI were calculated. The relationships among imaging techniques variables and their association with prognosis were evaluated using Pearson's chi-square test and the t-test. Receiver operator characteristic, Kaplan−Meier and Cox regression were used for the survival analysis. (3) Results: 54 patients were assessed. The median PFS and OS were 5 and 11 months, respectively. Significant strong relationships between volume-dependent variables obtained from PET/CT and CE-MRI were found (r > 0.750, p < 0.05). For OS, significant associations were found with SUVmax, SUVpeak, SUVmean and sphericity (HR: 1.17, p = 0.035; HR: 1.24, p = 0.042; HR: 1.62, p = 0.040 and HR: 0.8, p = 0.022, respectively). Among clinical variables, only Stupp protocol and age showed significant associations with OS and PFS. No CE-MRI derived variables showed significant association with prognosis. In multivariate analysis, age (HR: 1.04, p = 0.002), Stupp protocol (HR: 2.81, p = 0.001), multilesionality (HR: 2.20, p = 0.013) and sphericity (HR: 0.79, p = 0.027) derived from PET/CT showed independent associations with OS. For PFS, only age (HR: 1.03, p = 0.021) and treatment protocol (HR: 2.20, p = 0.008) were significant predictors. (4) Conclusions: 18F-fluorocholine PET/CT metabolic and radiomic variables were robust prognostic predictors in patients with IDH-wt high-grade gliomas, outperforming CE-MRI derived variables.

Failure of scintigraphy lymphatic mapping in endometrial cancer. Causes and solutions.

AIM: To evaluate the effect of technical problems and patient characteristics on sentinel lymph node (SLN) scintigraphic detection and mapping success in early stages of endometrial cancer (EC). METHODS: Patients with clinical early stage EC (IA-IB) underwent SLN mapping using technetium-99m-nanocolloid, between September 2011 and February 2020 were included. There were excluded cases with technical problems, 92 patients were included for the analysis of the diagnostic performance and the relation of mapping failure (pelvic unilateral or not detected SLN) with patient (age, body mass index, previous pelvic disease or surgery) and disease characteristics (histology, grade, myometrial invasion, lymphovascular space infiltration, tumor size, and lymphatic infiltration risk). RESULTS: The overall detection rate was 79%. Lymph node metastases were diagnosed in 7 patients. Age (P = .01), depth of myometrial invasion ≥50% (P = .04) and high risk of lymphatic infiltration (P = .02) were positively associated with mapping failure. In multivariate analysis, age was significantly associated with mapping failure [odds ratio = 1.63, 95%CI: 1.06-2.50; P = .027]. CONCLUSIONS: Age, depth of myometrial invasion and high risk of lymphatic infiltration were the factors associated with higher mapping failure. An individualized injection technique, optimizing the methodology, could minimize the detection failures.

Diagnostic methodology in labelled leukocyte scan for prosthetic / non-prosthetic osteoarticular infection: Visual or semi-quantitative analysis? One- or two-day protocol?

OBJECTIVE: as scarce literature on the topic is available, we aimed to compare diagnostic utility of semi-quantitative versus visual analysis in labelled white blood cell scintigraphy (WBCS) for osteoarticular infection. One-day and two-day protocols were assessed, particularly in orthopaedic devices. MATERIAL AND METHODS: prospective study of 79 consecutive patients with suspected osteoarticular infection. In all patients, WBCS were performed at 30min, 4h, 8h and 24h. Images were analysed by grouping in two protocols: one-day-protocol (experts evaluated 30min, 4h and 8h planar images) and two-day-protocol (experts evaluated 30min, 4h and 24h planar images). Planar images were interpreted qualitative and semiquantitatively and also were compared grouping patients with and without orthopaedic devices. To find which cut-off value of the percentage variation could predict of osteoarticular infection, multiple cut-off values were calculated in both protocols from the Youden index. Three blinded readers analysed the images. RESULTS: Comparing final diagnosis visual analysis of the one-day-protocol provided better results with sensitivity of 95.5%, specificity of 93% and diagnostic accuracy of 93.7% (p<001) than the two-day-protocol with values of 86.4%, 94.7% and 92.4%, respectively (p<001). For semi-quantitative analysis, the one-day-protocol also obtained better results with sensitivity of 72.7%, specificity of 78.9% and accuracy of 77.2% (p<001) than two-day-protocol (no significant results; p=0.14), especially in the group of patients with orthopaedic devices (sensitivity of 100%, specificity of 79.5% and accuracy of 82.7%; p<001). CONCLUSIONS: most accurate approach in the diagnosis of osteoarticular infection corresponded to visual analysis in one-day-protocol that showed greater sensitivity and specificity than semi-quantitative analysis. Semi-quantitative analysis only could be useful when visual analysis is doubtful. In patients with joint prostheses, an increase in percentage variation above 9% obtained maximum sensitivity and negative predictive value.

EANM recommendations based on systematic analysis of small animal radionuclide imaging in inflammatory musculoskeletal diseases.

Inflammatory musculoskeletal diseases represent a group of chronic and disabling conditions that evolve from a complex interplay between genetic and environmental factors that cause perturbations in innate and adaptive immune responses. Understanding the pathogenesis of inflammatory musculoskeletal diseases is, to a large extent, derived from preclinical and basic research experiments. In vivo molecular imaging enables us to study molecular targets and to measure biochemical processes non-invasively and longitudinally, providing information on disease processes and potential therapeutic strategies, e.g. efficacy of novel therapeutic interventions, which is of complementary value next to ex vivo (post mortem) histopathological analysis and molecular assays. Remarkably, the large body of preclinical imaging studies in inflammatory musculoskeletal disease is in contrast with the limited reports on molecular imaging in clinical practice and clinical guidelines. Therefore, in this EANM-endorsed position paper, we performed a systematic review of the preclinical studies in inflammatory musculoskeletal diseases that involve radionuclide imaging, with a detailed description of the animal models used. From these reflections, we provide recommendations on what future studies in this field should encompass to facilitate a greater impact of radionuclide imaging techniques on the translation to clinical settings.

Comparison of White Blood Cell Scintigraphy, FDG PET/CT and MRI in Suspected Diabetic Foot Infection: Results of a Large Retrospective Multicenter Study.

Diabetic foot infections (DFIs) represent one of the most frequent and disabling morbidities of longstanding diabetes; therefore, early diagnosis is mandatory. The aim of this multicenter retrospective study was to compare the diagnostic accuracy of white blood cell scintigraphy (WBC), 18F-fluorodeoxyglucose positron emission tomography/computed tomography ((18F) FDG PET/CT), and Magnetic Resonance Imaging (MRI) in patients with suspected DFI. Images and clinical data from 251 patients enrolled by five centers were collected in order to calculate the sensitivity, specificity, and accuracy of WBC, FDG, and MRI in diagnosing osteomyelitis (OM), soft-tissue infection (STI), and Charcot osteoarthropathy. In OM, WBC acquired following the European Society of Nuclear Medicine (EANM) guidelines was more specific and accurate than MRI (91.9% vs. 70.7%, p < 0.0001 and 86.2% vs. 67.1%, p = 0.003, respectively). In STI, both FDG and WBC achieved a significantly higher specificity than MRI (97.9% and 95.7% vs. 83.6%, p = 0.04 and p = 0.018, respectively). In Charcot, both MRI and WBC demonstrated a significantly higher specificity and accuracy than FDG (88.2% and 89.3% vs. 62.5%, p = 0.0009; 80.3% and 87.9% vs. 62.1%, p < 0.02, respectively). Moreover, in Charcot, WBC was more specific than MRI (89.3% vs. 88.2% p < 0.0001). Given the limitations of a retrospective study, WBC using EANM guidelines was shown to be the most reliable imaging modality to differentiate between OM, STI, and Charcot in patients with suspected DFI.

18F-choline PET/computed tomography and clinical parameters in the detection of significant prostate cancer in patients with increased prostate-specific antigen levels and previous negative biopsies.

OBJECTIVES: The aim of this study is to assess the value of the F-choline PET/computed tomography (CT) in predicting significant prostate cancer (sPCa) in patients with persistently increased prostate-specific antigen (PSA) levels and previous negative biopsies. To study the possible predictive added value of F-choline PET/CT to clinical variables and biomarkers derived from PSA in detecting sPCa. METHODS: We evaluated patients who underwent F-choline PET/CT because of ongoing suspicion of prostate cancer (PCa) due to elevated PSA levels (4-20 ng/mL) and at least one previous negative or no conclusive prostate biopsy for PCa. Age, PSA, free PSA, free/total PSA ratio, PSA velocity, PSA doubling time, PSA density and score risk were obtained. F-choline PET/CT was classified as negative/positive (PET-categorical). Additionally, we subclassified F-choline PET/CT according to the radiotracer uptake patterns (PET-pattern). The reference standard was the histological confirmation. Accuracy of PET/CT was evaluated. Univariate and multivariate logistic regression analyses were performed for metabolic and clinical variables. RESULTS: A total of 78 patients were included in our study, 23 had PCa (15 with sPCa). The PET pattern showed the highest accuracy and was the most powerful predictor of sPCa. In this research, the prediction of sPCa was improved combining PET pattern and score risk. CONCLUSION: F-choline PET/CT is a potential tool for predicting sPCa in patients with persistently increased PSA levels and previous negative biopsies, and also it could improve the performance of score risk in predicting sPCa.

Study of systemic disease IgG4. Usefulness of 2-[18F]-fluoro-2-deoxy-D-glucose -positron emission tomography/computed tomography for staging, selection of biopsy site, evaluation of treatment response and follow-up.

Immunoglobulin G4-related systemic disease (IgG4-RSD) is a recently emerging disorder characterized by swelling lesions with storiform fibrosis and lymphoplasmacytic infiltration enriched with IgG4-positive plasma cells. IgG4-RSD has been found in multiple organs/tissues. The diagnosis requires the integration of clinical, serological, imaging, histopathological, and immunohistological features. The 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (18F-FDG PET/CT) enables the acquisition of whole-body images and provides functional information about disease activity. However, its current role in IgG4-RSD is not well established in clinical practice. In our case, we studied a patient with systemic symptoms, submaxillary adenopathy, and imaging explorations that initially guided toward a lymphoproliferative process. However, the differential diagnosis with an autoimmune systemic disease type IgG4 was considered because of elevated levels of serum immunoglobulins. The study was completed with 18F-FDG PET/CT that not only allowed us to assess the extension disease and to locate the best lesion for biopsy but also allowed us to evaluate the response to treatment and to diagnose the suspicion of recurrence. In this case, PET/CT shows its usefulness in clinical practice.

Utility of 8 h and time decay-corrected acquisition scintigraphy with in-vitro labeled white blood cells for the diagnosis of osteoarticular infection.

INTRODUCTION: Except in the spine, labeled white-blood cell scintigraphy (WBCS) with image acquisition up to 24 h is the nuclear medicine test of choice for diagnosing osteoarticular infection. However, distinguishing between inflammation and infection is a challenge. OBJECTIVES: The first aim of this study was to verify earlier research studies that used 4 and 24 h time decay-corrected acquisition (TDCA) to differentiate infection from inflammation. The second aim was to analyze whether 8 h acquisition (1-day protocol) yielded similar results as 20-24 h acquisition. PATIENTS AND METHODS: This was an observational study of 94 patients (22-86 years, 52 women) with suspected osteoarticular infection referred to nuclear medicine to confirm infection. WBCS and TDCA images were obtained at 30 min, 4 h, and 8 h after injection of the labeled leukocytes, with collection times of 5, 8, and 12 min, respectively. Scintigrams were classified into three protocols: protocol 1: experts read only 30 min and 4 h images; protocol 2: experts read the whole set of images (30 min, 4 h, and 8 h) with different pixel intensities (each image normalized to its own maximum activity); protocol 3: experts read the whole set of images with the same pixel intensity. Sensitivity, specificity, positive and negative predictive values, and accuracy were calculated. In patients with orthopedic implants, the interobserver reproducibility for visual analysis was calculated using the κ index. RESULTS: Infection was confirmed in 26 cases. Sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and κ results were as follows: protocol 1: 92.3, 50.0, 41.4, 94.4, 61.7%, 0.79; protocol 2: 92.3, 94.1, 85.7, 97.0, 93.6%, 0.80; protocol 3: 96.2, 97.1, 92.6, 98.5, 96.8%, 0.77. CONCLUSION: TDCA acquisition of WBCS at 8 h (1-day protocol) enables a faster diagnosis than 24 h acquisition. The use of TDCA with the same pixel intensity in all images enables an accurate diagnostic of osteoarticular infection, with a considerable interobserver agreement for all protocols.