CD200+ fibroblasts form a pro-resolving mesenchymal network in arthritis.

Fibroblasts are important regulators of inflammation, but whether fibroblasts change phenotype during resolution of inflammation is not clear. Here we use positron emission tomography to detect fibroblast activation protein (FAP) as a means to visualize fibroblast activation in vivo during inflammation in humans. While tracer accumulation is high in active arthritis, it decreases after tumor necrosis factor and interleukin-17A inhibition. Biopsy-based single-cell RNA-sequencing analyses in experimental arthritis show that FAP signal reduction reflects a phenotypic switch from pro-inflammatory MMP3+/IL6+ fibroblasts (high FAP internalization) to pro-resolving CD200+DKK3+ fibroblasts (low FAP internalization). Spatial transcriptomics of human joints indicates that pro-resolving niches of CD200+DKK3+ fibroblasts cluster with type 2 innate lymphoid cells, whereas MMP3+/IL6+ fibroblasts colocalize with inflammatory immune cells. CD200+DKK3+ fibroblasts stabilized the type 2 innate lymphoid cell phenotype and induced resolution of arthritis via CD200-CD200R1 signaling. Taken together, these data suggest a dynamic molecular regulation of the mesenchymal compartment during resolution of inflammation.

Assessment of myocardial fibrosis in patients with systemic sclerosis using [68Ga]Ga-FAPI-04-PET-CT.

PURPOSE: Myocardial fibrosis (MF) is a factor of poor prognosis in systemic sclerosis (SSc). Direct in-vivo visualization of fibroblast activation as early readout of MF has not been feasible to date. Here, we characterize 68Gallium-labeled-Fibroblast-Activation-Inhibitor-04 ([68Ga]Ga-FAPI-04)-PET-CT as a diagnostic tool in SSc-related MF. METHODS: In this proof-of-concept trial, six SSc patients with and eight without MF of the EUSTAR cohort Erlangen underwent [68Ga]Ga-FAPI-04-PET-CT and cardiac MRI (cMRI) and clinical and serologic investigations just before baseline and during follow-up between January 2020 and December 2020. Myocardial biopsy was performed as clinically indicated. RESULTS: [68Ga]Ga-FAPI-04 tracer uptake was increased in SSc-related MF with higher uptake in SSc patients with arrhythmias, elevated serum-NT-pro-BNP, and increased late gadolinium enhancement (LGE) in cMRI. Histologically, myocardial biopsies from cMRI- and [68Ga]Ga-FAPI-04-positive regions confirmed the accumulation of FAP+ fibroblasts surrounded by collagen deposits. We observed similar but not equal spatial distributions of [68Ga]Ga-FAPI-04 uptake and quantitative cMRI-based techniques. Using sequential [68Ga]Ga-FAPI-04-PET-CTs, we observed dynamic changes of [68Ga]Ga-FAPI-04 uptake associated with changes in the activity of SSc-related MF, while cMRI parameters remained stable after regression of molecular activity and rather indicated tissue damage. CONCLUSIONS: We present first in-human evidence that [68Ga]Ga-FAPI-04 uptake visualizes fibroblast activation in SSc-related MF and may be a diagnostic option to monitor cardiac fibroblast activity in situ.

Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy.

OBJECTIVE: Activated synovial fibroblasts are key effector cells in RA. Selectively depleting these based upon their expression of fibroblast activation protein (FAP) is an attractive therapeutic approach. Here we introduce FAP imaging of inflamed joints using 68Ga-FAPI-04 in a RA patient, and aim to assess feasibility of anti-FAP targeted photodynamic therapy (FAP-tPDT) ex vivo using 28H1-IRDye700DX on RA synovial explants. METHODS: Remnant synovial tissue from RA patients was processed into 6 mm biopsies and, from several patients, into primary fibroblast cell cultures. Both were treated using FAP-tPDT. Cell viability was measured in fibroblast cultures and biopsies were evaluated for histological markers of cell damage. Selectivity of the effect of FAP-tPDT was assessed using flow cytometry on primary fibroblasts and co-cultured macrophages. Additionally, one RA patient intravenously received 68Ga-FAPI-04 and was scanned using PET/CT imaging. RESULTS: In the RA patient, FAPI-04 PET imaging showed high accumulation of the tracer in arthritic joints with very low background signal. In vitro, FAP-tPDT induced cell death in primary RA synovial fibroblasts in a light dose-dependent manner. An upregulation of cell damage markers was observed in the synovial biopsies after FAP-tPDT. No significant effects of FAP-tPDT were noted on macrophages after FAP-tPDT of neighbouring fibroblasts. CONCLUSION: In this study the feasibility of selective FAP-tPDT in synovium of rheumatoid arthritis patients ex vivo is demonstrated. Furthermore, this study provides the first indication that FAP-targeted PET/CT can be used to image arthritic joints, an important step towards application of FAP-tPDT as a targeted locoregional therapy for RA.

Changes over the years in radiopharmaceutical design.

Of the many uses of radiopharmaceuticals, developing radiotracers that contribute significantly to diagnosis and therapy of patients has been a major focus. This requires a broad spectrum of expertise including that of the attending physician who lends insight to an unmet clinical need neither addressed by other imaging techniques nor by analysis of tissue, blood, and urine for diagnostics and addressed by pharmaceuticals for therapeutic applications. The design criteria have depended on radiochemistry, on matching the radiopharmaceutical with the imaging devices, and basing the design on current pharmaceuticals. The chelates of technetium-99m were based on radiochemistry rather than clinical need yet are still used today in >70% of the clinical studies. Targeted radiotracers in neurologic and psychiatric disorders, inflammation, cardiovascular disease, and oncology have all been studied with the goal of determining the change in the density of a target protein as a function of disease or treatment or, especially in oncology, detection of the total extent of disease. In the latter approach, PET in university settings leads the way; however, the use of SPECT/CT has increased the specificity of SPECT imaging to complement the cost-effective generator and instant kits already available. Remarkable advances have been achieved in radionuclide therapy using theragnostic agents, with the exclusive domain of oncology. For this application the design of radionuclide therapy follows that used for diagnostics. The increased impact of the discipline depends on the opportunity to continue the search for the most appropriate radiopharmaceutical for each individual patient.

[Treatment strategy by radioiodine refractory differentiated thyroid cancer]. / Behandlungsstrategie beim radiojodrefraktären differenzierten Schilddrüsenkarzinom.

Traditionally, the multimodal therapy concept for differentiated thyroid carcinomas consists of thyroidectomy with neck dissection (for cN + neck) and adjuvant radioiodine ablation with subsequent risk-adapted TSH suppression. The extent of radioiodine uptake in metastatic thyroid carcinomas plays a significant role is significant in terms of prognosis. Radioiodine refractory lesions are characterized by the lack of radioiodine uptake in combination with the lack of decrease in the tumor marker thyroglobulin as well as signs of progression on imaging. Due to the mostly indolent course over a long period of time, a wait-and-see strategy in combination with local management of distant metastase symptom relief appears to be primarily sufficient. By evidence for change in tumor dynamics, the need for a multi-tyrosine kinase inhibitor (sorafenib, lenvatinib)-based systemic therapy should be thoroughly evaluated. These substances are mostly associated with an unfavorable side-effect profile (diarrhea, rash, arterial hypertension, local wound healing disorders), which leads to a non-negligible rate of treatment-associated morbidity and a high number of treatment interruptions. For this reason, two selective RET inhibitors (selpercatinib, pralsetinib) for differentiated thyroid carcinomas were approved by the FDA in 2020. A new perspective for the future would be the variable re-differentiation strategies, which aim to increase the sensitivity of tumor cells to radioiodine.

Resolution of vascular inflammation in patients with new-onset giant cell arteritis: data from the RIGA study.

OBJECTIVES: Efficacy evaluation of GCA treatment is primarily based on non-specific symptoms and laboratory markers. We aimed to assess the change in vascular inflammation in patients with large vessel (LV)-GCA under different treatments using [18F]FDG PET/CT. METHODS: Observational study on patients with new-onset, active LV-GCA starting treatment with either prednisolone monotherapy (PRED) or combination with MTX or tocilizumab (TOC). All patients underwent baseline and follow-up PET/CT. The aorta and its major branches were assessed using PET vascular activity score (PETVAS) by independent readers. Cumulative glucocorticoid doses and cessation of glucocorticoid treatment were documented in all patients. RESULTS: We included 88 LV-GCA patients, 27 were treated with PRED, 42 with MTX and 19 with TOC. PETVAS decreased from 18.9-8.0 units at follow-up in the overall population (P <0.001). PETVAS changes were numerically higher in patients receiving MTX (-12.3 units) or TOC (-11.7 units) compared with PRED (-8.7). Mean cumulative prednisolone dosages were 5637, 4418 and 2984 mg in patients treated with PRED, MTX and TOC (P =0.002). Risk ratios for glucocorticoid discontinuation at the time of follow-up PET/CT were 6.77 (95% CI: 1.01, 45.29; P =0.049) and 16.25 (95% CI: 2.60, 101.73; P =0.003) for MTX and TOC users compared with PRED users. CONCLUSION: Treatment of LV-GCA inhibits vascular inflammation in the aorta and its major branches. While similar control of vascular inflammation was achieved with PRED, MTX and TOC treatments, TOC showed a strong glucocorticoid sparing effect, supporting the concept of initial combination therapy.

Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging.

OBJECTIVES: To date, there is no valuable tool to assess fibrotic disease activity in humans in vivo in a non-invasive way. This study aims to uncouple inflammatory from fibrotic disease activity in fibroinflammatory diseases such as IgG4-related disease. METHODS: In this cross-sectional clinical study, 27 patients with inflammatory, fibrotic and overlapping manifestations of IgG4-related disease underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP; 68Ga-FAP inhibitor (FAPI)-04), 18F-fluorodeoxyglucose (FDG), MRI and histopathological assessment. In a longitudinal approach, 18F-FDG and 68Ga-FAPI-04 PET/CT data were evaluated before and after immunosuppressive treatment and correlated to clinical and MRI data. RESULTS: Using combination of 68Ga-FAPI-04 and 18F-FDG-PET, we demonstrate that non-invasive functional tracking of IgG4-related disease evolution from inflammatory towards a fibrotic outcome becomes feasible. 18F-FDG-PET positive lesions showed dense lymphoplasmacytic infiltration of IgG4+ cells in histology, while 68Ga-FAPI-04 PET positive lesions showed abundant activated fibroblasts expressing FAP according to results from RNA-sequencing of activated fibroblasts. The responsiveness of fibrotic lesions to anti-inflammatory treatment was far less pronounced than that of inflammatory lesions. CONCLUSION: FAP-specific PET/CT permits the discrimination between inflammatory and fibrotic activity in IgG4-related disease. This finding may profoundly change the management of certain forms of immune-mediated disease, such as IgG4-related disease, as subtypes dominated by fibrosis may require different approaches to control disease progression, for example, specific antifibrotic agents rather than broad spectrum anti-inflammatory treatments such as glucocorticoids.

Correction to: Assessment of treatment responses in children and adolescents with Ewing sarcoma with metabolic tumor parameters derived from 18F-FDG-PET/CT and circulating tumor DNA.

The author names and family names of the originally published article was inversed. Correct presentation is presented here.

Assessment of treatment responses in children and adolescents with Ewing sarcoma with metabolic tumor parameters derived from 18F-FDG-PET/CT and circulating tumor DNA.

PURPOSE: The purpose of this study was to perform a prospective integrated analysis of 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET)/computed tomography (CT) and circulating tumor DNA (ctDNA) to assess responses to multimodal chemotherapy in children and adolescents suffering from Ewing sarcoma (EwS). METHODS: A total of 20 patients with histologically confirmed EwS underwent multiple 18F-FDG-PET/CT, performed at the time of each patient's initial diagnosis and after the second and fifth induction chemotherapy block (EWING2008 treatment protocol, NCT00987636). Additional PET examinations were performed as clinically indicated in some patients, e.g., in patients suspected of having progressive or relapsing disease. All 263 18F-FDG-positive lesions in the field of view suggestive of tumor tissue were assessed quantitatively to calculate PET-derived parameters, including whole-body metabolic tumor volume (wb-MTV) and whole-body total lesion glycolysis (wb-TLG), as well as the following data: standardized uptake value (SUV)max and SUVmean. Tumor-specific ctDNA in patient plasma samples was quantified using digital droplet PCR (ddPCR), and the correlations between ctDNA levels and PET-derived parameters were analyzed. Metabolic responses to multimodal chemotherapy as assessed with PET-parameters were compared to biochemical responses as assessed with changes in ctDNA levels. RESULTS: Twenty patients underwent a total of 87 18F-FDG-PET/CT scans, which detected 263 FDG-positive tumor lesions. Significant correlations between SUVmax, SUVmean, wb-MTV and wb-TLG values, and ctDNA levels were observed (all p < 0.0001). All patients suffering from EwS, with histology serving as gold standard, also presented with a positive corresponding ctDNA sample and a positive 18F-FDG-PET/CT examination before initiation of therapy. There were no false-negative results. Evaluation of treatment response after the fifth block of induction chemotherapy showed that the agreement between the metabolic response and biochemical response was 90%, which was statistically significant (Cohen κ = 0.62; p < 0.05). Non-detectable ctDNA after the second block of induction chemotherapy was associated with complete biochemical and metabolic responses after the fifth block of induction chemotherapy in 16/17 patients (94%). During a median follow-up period of 36 months (range: 8-104 months), four patients had tumor relapses, which, in all cases, were accompanied by an increase in plasma ctDNA levels and a positive 18F-FDG-PET/CT. No false-negative results were observed in the study cohort. Complete biochemical and metabolic responses after the fifth block of induction chemotherapy had a high positive predictive value for disease remission during the follow-up period; specifically, the positive predictive value was 88%. CONCLUSION: The combination of 18F-FDG-PET/CT and ctDNA quantification is a very promising noninvasive tool for assessing treatment responses and detecting tumor relapses in children and young adolescents suffering from EwS who are undergoing multimodal chemotherapy.

Development of 18F-Fluoroglycosylated PSMA-Ligands with Improved Renal Clearance Behavior.

The prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is highly expressed in the malignant human prostate epithelium. Therefore, PSMA has emerged as a very attractive target for developing radiopharmaceuticals for the diagnosis, e.g., by positron emission tomography (PET) imaging, and radiotherapy of prostate cancer. The aim of this study was to develop 18F-labeled PSMA ligands bearing different 18F-glycosyl moieties to study the effect on the in vivo clearance behavior of radiotracers in addition to their tumor binding ability. Therefore, we applied click chemistry-based 18F-fluoroglcosylation using 2-deoxy-2-[18F]fluoroglucosyl azide or 6-deoxy-6-[18F]fluoroglucosyl azide as prosthetic groups for the radiosynthesis of the 18F-fluoroglycosylated glutamate-urea-lysine-based PSMA inhibitors 2-[18F]FGlc-PSMA ([18F]7) and 6-[18F]FGlc-PSMA ([18F]8). The PSMA inhibitory potencies were determined by competitive radioligand binding assays using 99mTc-MIP-1404 and PSMA-expressing PC-3 PIP cells, revealing moderate PSMA inhibitory potencies for [18F]7 (IC50 = 234 nM) and [18F]8 (IC50 = 59 nM). Biodistribution and small-animal PET studies were performed using PSMA-positive PC-3 PIP and PSMA-negative PC-3 tumor-bearing nude mice. PSMA inhibitors [18F]7 and [18F]8 were obtained in high radioactivity yields of 19-22% (nondecay-corrected, referred to [18F]fluoride) and with molar activities of 71-136 GBq/µmol. In the biodistribution studies, the uptake levels of [18F]7 and [18F]8 in PC-3 PIP tumors were 13 ± 3%ID/g and 6 ± 5%ID/g at 60 min p.i., respectively. PSMA-negative PC-3 tumors and all other tissues had negligible low uptake values. Interestingly, [18F]7 had high uptake in the kidneys, with remarkable retention from 30 to 60 min p.i. (74 to 72%ID/g). In contrast, [18F]8 revealed a low uptake of 7.5%ID/g in the kidneys at 30 min p.i. and was rapidly cleared through the kidney (0.9%ID/g at 120 min p.i.). In direct comparison to a 68Ga-PSMA-11 PET scan of the same mouse, [18F]7 and [18F]8 showed 2- to 3-fold higher uptake values in PC-3 PIP tumors. Both radiotracers were solely cleared via the kidneys and not via the hepatobiliary pathway. The regional kidney distribution pattern of the tracers in the kidneys revealed that 68Ga-PSMA-11 and 2-[18F]FGlc-PSMA([18F]7) mainly accumulated in the cortex of the kidneys, whereas 6-[18F]FGlc-PSMA([18F]8) showed a 10-fold lower kidney uptake with accumulation in the inner medulla or pelvis of the kidneys. Overall, the developed 6-fluoroglucosyl derivative [18F]8, with its considerably low kidney uptake and fast clearance, demonstrated high uptake in PSMA-positive tumors in vivo. This candidate could, therefore, be valuable for translation into the clinic.

Quantitative SPECT/CT-Technique and Clinical Applications.

The continuous development of SPECT over the past 50 years has led to improved image quality and increased diagnostic confidence. The most influential developments include the realization of hybrid SPECT/CT devices, as well as the implementation of attenuation correction and iterative image reconstruction techniques. These developments have led to a preference for SPECT/CT devices over SPECT-only systems and to the widespread adoption of the former, strengthening the role of SPECT/CT as the workhorse of Nuclear Medicine imaging. New trends in the ongoing development of SPECT/CT are diverse. For example, whole-body SPECT/CT images, consisting of acquisitions from multiple consecutive bed positions in the manner of PET/CT, are increasingly performed. Additionally, in recent years, some interesting approaches in detector technology have found their way into commercial products. For example, some SPECT cameras dedicated to specific organs employ semiconductor detectors made of cadmium telluride or cadmium zinc telluride, which have been shown to increase the obtainable image quality by offering a higher sensitivity and energy resolution. However, the advent of quantitative SPECT/CT which, like PET, can quantify the amount of tracer in terms of Bq/mL or as a standardized uptake value could be regarded as most important development. It is a major innovation that will lead to increased diagnostic accuracy and confidence, especially in longitudinal studies and in the monitoring of treatment response. The current work comprises two main aspects. At first, physical and technical fundamentals of SPECT image formation are described and necessary prerequisites of quantitative SPECT/CT are reviewed. Additionally, the typically achievable quantitative accuracy based on reports from the literature is given. Second, an extensive list of studies reporting on clinical applications of quantitative SPECT/CT is provided and reviewed.

Effect of reduced photon count levels and choice of normal data on semi-automated image assessment in cardiac SPECT.

BACKGROUND: The SMARTZOOM multifocal collimator from Siemens Healthcare was developed to improve the γ-photon sensitivity in myocardial perfusion imaging without truncating the field of view. As part of the IQ-SPECT package, it may be used to reduce radiopharmaceutical dose to patients, as well as acquisition time. The aim of this study was twofold: (1) to evaluate the influence of dose reduction in semi-automated MPI scoring, with focus on different strategies for the choice of normal data (count-matched, full-count), and (2) to evaluate the effect of dose reduction afforded by Siemens' IQ-SPECT package. METHODS: 50 patients underwent Tc-99m-sestamibi one-day stress/rest SPECT/CT. Multiple levels of count reduction were generated using binomial thinning. Using Corridor 4DM, summed stress score (SSS) was calculated using either count-matched or full-count normal data. Studies were classified as low-risk (SSS < 4) or intermediate/high-risk (SSS ≥ 4). RESULTS: Count reduction using count-matched normal data increases false-normal rate and decreases sensitivity. With full-count normal data, count reduction increases false-hypoperfusion rate, leading to decreased specificity. Altogether, rate of reclassification was significant at roughly 67% dose and below. CONCLUSION: Significant bias results from count level of normal data relative to actual patient data. Compared to standard LEHR, IQ-SPECT should allow for significant dose reduction.

Single-cycle induction chemotherapy before chemoradiotherapy or surgery in functionally inoperable head and neck squamous cell carcinoma: 10-year results.

INTRODUCTION: The response to induction chemotherapy (IC) predicts local control after conservative treatment of laryngeal, meso- and hypopharyngeal head and neck squamous cell carcinoma (HNSCC) and can thus help to avoid surgery. Single-cycle induction chemotherapy may help to maintain a low local recurrence rate while keeping the overall toxicity manageable. However, long-term data on single-cycle IC response by tumor location is lacking. METHODS: N = 102 patients with functionally inoperable primary HNSCC of the larynx (n = 43), hypopharynx (n = 42) or mesopharynx/tongue (n = 17) received one cycle of docetaxel (75 mg/m2, d1) plus cisplatin (30 mg/m2, d1-3) or carboplatin (AUC 1.5, d1-3) and a response evaluation 3 weeks later. Responders (≥ 30% tumor size reduction and ≥ 20% SUVmax decrease in 18F-FDG PET/CT) were recommended chemoradiotherapy (CRT), and non-responders surgery. RESULTS: The overall response rate was 72.5%. All 74 responders and 10 non-responders received primary CRT, and 18 patients received primary surgery after single-cycle IC. Overall 10-year local recurrence-free survival (LRFS) was 73.7%. Three-year LRFS was 88.2% (mesopharynx/tongue), 88.2% (larynx), and 73.3% (hypopharynx); p = 0.17. 3-year distant metastasis-free survival (DMFS) was 94.1% (mesopharynx/tongue), 88.0% (larynx) and 76.4% (hypopharynx); p > 0.05. This influenced the 3-year cancer-specific survival (CSS) for larynx (91.2%) vs. hypopharynx tumors (60.8%); p = 0.003, but CSS was not different to tumors in the mesopharynx/tongue (81.4%); p > 0.05. CONCLUSIONS: A single-cycle induction chemotherapy for HNSCC enables surgery plus adjuvant therapy as well as chemoradiotherapy. The long-term local and distant disease control was good but varied between tumors in the larynx and mesopharynx/tongue vs. hypopharynx.

Growth rates of malignant and benign thyroid nodules in an ultrasound follow-up study: a retrospective cohort study.

BACKGROUND: Thyroid nodules are frequently detected by cervical ultrasound examinations. In follow-up studies, malignant as well as benign nodules may exhibit an increase in size. The objective of our investigation was to test whether histologically determined malignant and benign thyroid nodules show differences in growth rates above a defined significance level. METHODS: A retrospective ultrasound cohort follow-up study from 4 to 132 months included 26 patients with differentiated carcinomas and 26 patients with adenomas of the thyroid gland. Significance levels were determined by intra- and interobserver variations of volumetric measurements in 25 individuals. RESULTS: Intra- and interobserver volumetric measurements were highly correlated (r = 0.99 and r = 0.98, respectively), with variations of 28 and 40%, respectively. The growth rates of malignant and benign nodules did not show differences with respect to two sonographic measurements (d = - 0.04, 95%CI(P): 0.41-0.85, P = 0.83). Using shorter increments and multiple measurements, growth rates of malignant nodules revealed significantly higher values (d = 0.16, 95%CI(P): 0.02-0.04, P = 0.039). CONCLUSIONS: The growth rates of benign and malignant thyroid nodules do not appear to differ using two sonographic volumetric measurements. However, due to temporal changes in cellular proliferation and arrest, malignant nodules may exhibit higher growth rates with multiple assessments and shorter increments.

Quantitative radionuclide imaging of bone metastases.

By improving the localization of foci of pathological tracer uptake and offering information on their computed tomography (CT) morphology, single photon emission computed tomography (SPECT)/CT hybrid imaging has considerably improved the diagnostic accuracy of skeletal scintigraphy. SPECT/CT also has the potential to measure tracer uptake in vivo in absolute units. The present article reviews the methodology for and the potential clinical impact of quantitative skeletal scintigraphy.

99m Tc-MIP-1404-SPECT/CT for the detection of PSMA-positive lesions in 225 patients with biochemical recurrence of prostate cancer.

BACKGROUND: 99m Tc-MIP-1404 (Progenics Pharmaceuticals, Inc., New York, NY) is a novel, SPECT-compatible 99m Tc-labeled PSMA inhibitor for the detection of prostate cancer. We present results of its clinical use in a cohort of 225 men with histologically confirmed prostate cancer referred for workup of biochemical relapse. METHODS: From April 2013 to April 2017, 99m Tc-MIP1404-scintigraphy was performed in 225 patients for workup of PSA biochemical relapse of prostate cancer. Whole-body planar and SPECT/CT images of the lower abdomen and thorax were obtained 3-4 h p.i. of 710 ± 64 MBq 99m Tc-MIP-1404. Images were visually analyzed for presence and location of abnormal uptake. In addition, quantitative analysis of the SPECT/CT data was carried out on a subset of 125 patients. Follow-up reports of subsequent therapeutic interventions were available for 59% (139) of all patients. RESULTS: Tracer-positive lesions were detected in 77% (174/225) of all patients. Detections occurred at the area of local recurrence in the prostate in 25% of patients (or a total of 56), with metastases in lymph nodes in 47% (105), bone in 27% (60), lung in 5% (12), and other locations in 2% (4) of patients. Detection rates were 90% at PSA levels ≥2 ng/mL and 54% below that threshold. Lesional SUVmax values were, on average, 32.2 ± 29.6 (0.8-142.2), and tumor-to-normal ratios 146.6 ± 160.5 (1.9-1482.4). The PSA level correlated significantly with total uptake of MIP-1404 in tumors (P < 0.001). Furthermore, total tumor uptake was significantly higher in patients with Gleason scores ≥8 compared to those with Gleason scores ≤7 (P < 0.05). In patients with androgen deprivation therapy, the detection rate was significantly higher compared to patients without androgen deprivation therapy (86% vs 71%, P < 0.001). Based on 99m Tc-MIP-1404-imaging and other information, an interdisciplinary tumor board review recommended changes to treatment plans in 74% (104/139) of those patients for whom the necessary documentation was available. CONCLUSION: SPECT/CT with 99m Tc-labeled MIP-1404 has a high probability in detecting PSMA-positive lesions in patients with elevated PSA. Statistical analysis disclosed significant relationship between quantitative 99m Tc-MIP-1404 uptake, PSA level, and Gleason score.

The value of 18F-FDG-PET/CT in identifying the cause of fever of unknown origin (FUO) and inflammation of unknown origin (IUO): data from a prospective study.

BACKGROUND: Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are diagnostically challenging conditions. Diagnosis of underlying disease may be improved by 18F-fluorodesoxyglucose positron emission tomography (18F-FDG-PET). METHODS: Prospective study to test diagnostic utility of 18F-FDG-PET/CT in a large cohort of patients with FUO or IUO and to define parameters that increase the likelihood of diagnostic 18F-FDG-PET/CT. Patients with FUO or IUO received 18F-FDG-PET/CT scanning in addition to standard diagnostic work-up. 18F-FDG-PET/CT results were classified as helpful or non-helpful in establishing final diagnosis. Binary logistic regression was used to identify clinical parameters associated with a diagnostic 18F-FDG-PET/CT. RESULTS: 240 patients were enrolled, 72 with FUO, 142 with IUO and 26 had FUO or IUO previously (exFUO/IUO). Diagnosis was established in 190 patients (79.2%). The leading diagnoses were adult-onset Still's disease (15.3%) in the FUO group, large vessel vasculitis (21.1%) and polymyalgia rheumatica (18.3%) in the IUO group and IgG4-related disease (15.4%) in the exFUO/IUO group. In 136 patients (56.7% of all patients and 71.6% of patients with a diagnosis), 18F-FDG-PET/CT was positive and helpful in finding the diagnosis. Predictive markers for a diagnostic 18F-FDG-PET/CT were age over 50 years (p=0.019), C-reactive protein (CRP) level over 30 mg/L (p=0.002) and absence of fever (p=0.001). CONCLUSION: 18F-FDG-PET/CT scanning is helpful in ascertaining the correct diagnosis in more than 50% of the cases presenting with FUO and IUO. Absence of intermittent fever, higher age and elevated CRP level increase the likelihood for a diagnostic 18F-FDG-PET/CT.