Differences in Distribution and Detection Rate of the [68Ga]Ga-PSMA Ligands PSMA-617, -I&T and -11—Inter-Individual Comparison in Patients with Biochemical Relapse of Prostate Cancer

The biochemical relapse of prostate cancer is diagnostically challenging but of high clinical impact for subsequent patient treatment. PET/CT with radiolabeled PSMA ligands outperforms conventional diagnostic methods in the detection of tumor recurrence. Several radiopharmaceuticals were and are available for use. The aim of this study was to investigate whether the routinely applied [68Ga]Ga-PSMA ligands PSMA-617, -I&T and -11 (HBED-CC) differ in physiological and pathological distribution, or in tumor detection rate. A retrospective evaluation of 190 patients (39 patients received PSMA-617, 68 patients PSMA-I&T and 83 patients PSMA-11) showed significant differences in tracer accumulation within all organs examined. The low retention within the compartments blood pool, bone and muscle tissue is a theoretical advantage of PSMA-11. Evaluation of tumor lesion uptake and detection rate did not reveal superiority of one of the three radiopharmaceuticals, neither in the whole population, nor in particularly challenging subgroups like patients with very low PSA levels. We conclude that all three [68Ga]Ga-PSMA ligands are equally feasible in this clinically important scenario, and may replace each other in case of unavailability or production restrictions.

Imaging angiogenesis in atherosclerosis in large arteries with 68Ga-NODAGA-RGD PET/CT: relationship with clinical atherosclerotic cardiovascular disease

Background Integrin alpha-V-beta-3 (αvβ3) pathway is involved in intraplaque angiogenesis and inflammation and represents a promising target for molecular imaging in cardiovascular diseases such as atherosclerosis. The aim of this study was to assess the clinical correlates of arterial wall accumulation of 68Ga-NODAGA-RGD, a specific αvβ3 integrin ligand for PET. Materials and methods The data of 44 patients who underwent 68Ga-NODAGA-RGD PET/CT scans were retrospectively analyzed. Tracer accumulation in the vessel wall of major arteries was analyzed semi-quantitatively by blood-pool-corrected target-to-background ratios. Tracer uptake was compared with clinically documented atherosclerotic cardiovascular disease, cardiovascular risk factors and calcified plaque burden. Data were compared using the Mann–Whitney U test, Pearson correlation and Spearman correlation. Results 68Ga-NODAGA-RGD arterial uptake was significantly higher in patients with previous clinically documented atherosclerotic cardiovascular disease (mean TBR 2.44 [2.03–2.55] vs. 1.81 [1.56–1.96], p = 0.001) and showed a significant correlation with prior cardiovascular or cerebrovascular event (r = 0.33, p = 0.027), BMI (ρ = 0.38, p = 0.01), plaque burden (ρ = 0.31, p = 0.04) and hypercholesterolemia (r = 0.31, p = 0.04). Conclusions 68Ga-NODAGA-RGD holds promise as a non-invasive marker of disease activity in atherosclerosis, providing information about intraplaque angiogenesis.

CPPs to the Test: Effects on Binding, Uptake and Biodistribution of a Tumor Targeting Nanobody

Nanobodies are well-established targeting ligands for molecular imaging and therapy. Their short circulation time enables early imaging and reduces systemic radiation exposure. However, shorter circulation time leads to lower tracer accumulation in the target tissue. Cell-penetrating peptides (CPPs) improve cellular uptake of various cargoes, including nanobodies. CPPs could enhance tissue retention without compromising rapid clearance. However, systematic investigations on how the functionalities of nanobody and CPP combine with each other at the level of 2D and 3D cell cultures and in vivo are lacking. Here, we demonstrate that conjugates of the epidermal growth factor receptor (EGFR)-binding nanobody 7D12 with different CPPs (nonaarginine, penetratin, Tat and hLF) differ with respect to cell binding and induction of endocytosis. For nonaarginine and penetratin we compared the competition of EGF binding and performance of L- and D-peptide stereoisomers, and tested the D-peptide conjugates in tumor cell spheroids and in vivo. The D-peptide conjugates showed better penetration into spheroids than the unconjugated 7D12. Both in vivo and in vitro, the behavior of the agent reflects the combination of both functionalities. Although CPPs cause promising increases in in vitro uptake and 3D penetration, the dominant effect of the CPP in the control of biodistribution warrants further investigation.

Imaging Angiogenesis in Atherosclerosis in Large Arteries with 68Ga-NODAGA-RGD PET/CT: Relationship with Clinical Atherosclerotic Cardiovascular Disease

BackgroundIntegrin alpha-V-beta-3 (αvβ3) pathway is involved in intraplaque angiogenesis and inflammation and represents a promising target for molecular imaging in cardiovascular diseases such as atherosclerosis. The aim of this study was to assess the clinical correlates of arterial wall accumulation of 68Ga-NODAGA-RGD, a specific αvβ3 integrin ligand for PET. Materials and methodsThe data of 44 patients who underwent 68Ga-NODAGA-RGD PET/CT scans were retrospectively analyzed. Tracer accumulation in the vessel wall of major arteries was analyzed semi-quantitatively by blood-pool-corrected target-to-background ratios. Tracer uptake was compared with clinically documented atherosclerotic cardiovascular disease, cardiovascular risk factors and calcified plaque burden. Data were compared using the Mann-Whitney U test and Spearman correlation. Results68Ga-NODAGA-RGD arterial uptake was significantly higher in patients with previous clinically documented atherosclerotic cardiovascular disease (mean TBR 2.44 [2.03-2.55] vs. 1.81 [1.56-1.96], p = 0.001) and showed a significant correlation with prior cardiovascular or cerebrovascular event (r = 0.34, p = 0.024), BMI (r = 0.38, p = 0.01), plaque burden (r = 0.31, p = 0.04), and hypercholesterolemia (r= 0.31, p = 0.04).Conclusions68Ga-NODAGA-RGD holds promise as a non-invasive marker of disease activity in atherosclerosis, providing information about intraplaque angiogenesis.

Spontaneous cervical swelling syndrome as a rare cause of neck edema: case series and literature review

ABSTRACT Spontaneous cervical swelling syndrome (SCSS) is a rare disorder characterized by unprovoked, self-limiting and often unilateral cervical edema. SCSS is a recurrent disorder that predominantly affects adult women and is not associated with laboratory abnormalities. We report on eight female patients with a mean age of 56 (38–82) years at the time of the first presentation. The episodes were characterized by an acute onset in all patients and had a mean duration of 3.8 (1–7) days. Biochemical analysis did not reveal any related abnormalities. Imaging of the neck and chest demonstrated diffuse edema in the supraclavicular fossa and left infrahyoid region in all patients. At the time of the acute event, lymphatic scintigraphy revealed tracer accumulation in the left supraclavicular region in three patients and could not demonstrate any abnormalities in the in-between episodes in two patients.

18F-Trifluoromethylated D-Cysteine as a Promising New PET Tracer for Glioma Imaging: Comparative Analysis With MRI and Histopathology in Orthotopic C6 Models

Comparing MRI and histopathology, this study aims to comprehensively explore the potential application of 18F-trifluoromethylated D-cysteine (S-[18F]CF3-D-CYS) in evaluating glioma by using orthotopic C6 glioma models. Sprague–Dawley (SD) rats (n = 9) were implanted with C6 glioma cells. Tumor growth was monitored every week by multiparameter MRI [including dynamic contrast-enhanced MRI (DCE-MRI)], [18F]FDG, S-[18F]CF3-D-CYS, and [18F]FDOPA PET imaging. Repeated scans of the same rat with the two or three [18F]-labeled radiotracers were investigated. Initial regions of interest were manually delineated on T2WI and set on the same level of PET images, and tumor-to-normal brain uptake ratios (TNRs) were calculated to semiquantitatively assess the tracer accumulation in the tumor. The tumor volume in PET and histopathology was calculated. HE and Ki67 immunohistochemical staining were further performed. The correlations between the uptake of S-[18F]CF3-D-CYS and Ki67 were analyzed. Dynamic S-[18F]CF3-D-CYS PET imaging showed tumor uptake rapidly reached a peak, maintained plateau during 10–30 min after injection, then decreased slowly. Compared with [18F]FDG and [18F]FDOPA PET imaging, S-[18F]CF3-D-CYS PET demonstrated the highest TNRs (P < 0.05). There were no significant differences in the tumor volume measured on S-[18F]CF3-D-CYS PET or HE specimen. Furthermore, our results showed that the uptake of S-[18F]CF3-D-CYS was significantly positively correlated with tumor Ki67, and the poor accumulated S-[18F]CF3-D-CYS was consistent with tumor hemorrhage. There was no significant correlation between the S-[18F]CF3-D-CYS uptakes and the Ktrans values derived from DCE-MRI. In comparison with MRI and histopathology, S-[18F]CF3-D-CYS PET performs well in the diagnosis and evaluation of glioma. S-[18F]CF3-D-CYS PET may serve as a valuable tool in the clinical management of gliomas.

Persistent hyperthyroidism in a patient after total thyroidectomy: the thyroid anatomy has implications for treatment

Introduction. Grave’s disease (GD) can be treated using three modalities: anti-thyroid medications, radioactive iodine therapy (RAI), or surgery. If surgery is selected, total thyroidectomy is the procedure of choice. Patients with hyperthyroidism frequently have an enlarged thyroid gland, occasionally with a pyramidal lobe. Aim. We point the usefulness of thyroid scintigraphy, which provides valuable information regarding the thyroid anatomy. Description of the case. The manuscript presents a case report of 43-year-old woman with unstable Grave’s disease, who underwent thyroidectomy and developed persistent hyperthyroidism postoperatively. She was referred by an endocrinologist to a nuclear medicine outpatient clinic for RAI therapy. I-iodide scintigraphy revealed two foci with excessive tracer accumulation. One of the foci in the middle of the neck corresponded to the pyramidal lobe. Conclusion. The thyroid anatomy anomalies can lead to unnecessary implications for treatment. Identifying the pyramidal lobe preoperatively and removing it from patients requiring total thyroidectomy may decrease the recurrence rate of hyperthyroidism. Thyroid scintigraphy is a useful diagnostic tool to visualize the pyramidal lobe.

18F-THK5351 PET imaging in patients with progressive supranuclear palsy: associations with core domains and diagnostic certainty

The associations of 18F-THK5351 tau positron emission tomography (PET) findings with core domains of progressive supranuclear palsy (PSP) and its diagnostic certainty have yet to be fully elucidated. The 18F-THK5351 PET patterns of 17 patients with PSP (68.9 ± 6.5 years; 8 women) were compared with those observed in 28 age-matched and sex-matched (66.2 ± 4.5 years, 18 women) control subjects (CS). Tracer accumulation—as reflected by standardized uptake value ratios (SUVRs) and z-scores—was correlated with core domains of PSP and different levels of diagnostic certainty. Compared with CS, patients with PSP showed an increased 18F-THK5351 uptake in the globus pallidus and red nucleus. Patients with PSP and oculomotor dysfunction had significantly higher SUVRs in the midbrain, red nucleus, and raphe nucleus than those without. In addition, cases who meet criteria for level 1 (highest) certainty in the postural instability domain showed significantly higher SUVRs in the frontal, parietal, precuneus, and sensory-motor cortex. Patients with probable PSP had significantly higher SUVR values than those with possible PSP in multiple cortical (i.e., frontal, parietal, temporal, anterior cingulate gyrus, precuneus, and sensory-motor gyrus) and subcortical (i.e., putamen, thalamus, and raphe nucleus) regions. Patterns of 18F-THK5351 uptake were correlated to core domains of PSP—including oculomotor dysfunction and postural instability. Moreover, the degree of diagnostic certainty for PSP was appreciably associated with 18F-THK5351 PET findings.

Analysis of failed therapy evaluations in radioembolization of primary and secondary liver cancers

Purpose To analyze patients’ characteristics and reasons for not performing planned transarterial radioembolization (TARE) in liver cancer after 99mTc-labeled macroaggregated albumin (99mTc-MAA) evaluation. Methods In this retrospective single-center cohort, all patients undergoing 99mTc-MAA evaluation prior to planned TARE for primary or secondary liver cancer between 2009 and 2018 were analyzed. Patients were assigned to either “TARE” or “no TARE” group. Patients’ characteristics, arising reasons for not performing the planned TARE treatment as well as predictive factors for occurrence of these causes were analyzed. Results 436 patients [male = 248, female = 188, median age 62 (23–88) years] with 99mTc-MAA evaluation prior to planned TARE of primary or secondary liver cancer were included in this study. 148 patients (33.9%) did not receive planned TARE. Patients with a hepatic tumor burden > 50%, no liver cirrhosis, no previous therapies and a higher bilirubin were significantly more frequent in “no TARE” compared to “TARE” group. Main reasons for not performing TARE were extrahepatic tracer accumulation (n = 70, 40.5%), non-target accumulation of 99mTc-MAA (n = 27, 15.6%) or a hepatopulmonary shunt fraction of more than 20% (n = 23, 13.3%). Independent preprocedural parameters for not performing planned TARE were elevated bilirubin (p = 0.021) and creatinine (p = 0.018) and lower MELD score (p = 0.031). Conclusion A substantial number of patients are precluded from TARE following 99mTc-MAA evaluation, which is, therefore, implicitly needed to determine contraindications to TARE and should not be refrained from in pretreatment process. However, a preceding careful patient selection is needed especially in patients with high hepatic tumor burden and alteration in lab parameters.

Attempts to Target Staphylococcus aureus Induced Osteomyelitis Bone Lesions in a Juvenile Pig Model by Using Radiotracers

Background [18F]FDG Positron Emission Tomography cannot differentiate between sterile inflammation and infection. Therefore, we, aimed to develop more specific radiotracers fitted for differentiation between sterile and septic infection to improve the diagnostic accuracy. Consequently, the clinicians can refine the treatment of, for example, prosthesis-related infection. Methods: We examined different target points; Staphylococcus aureus biofilm (68Ga-labeled DOTA-K-A9 and DOTA-GSGK-A11), bone remodeling ([18F]NaF), bacterial cell membranes ([68Ga]Ga-Ubiquicidin), and leukocyte trafficking ([68Ga]Ga-DOTA-Siglec-9). We compared them to the well-known glucose metabolism marker [18F]FDG, in a well-established juvenile S. aureus induced osteomyelitis (OM) pig model. Results: [18F]FDG accumulated in the OM lesions seven days after bacterial inoculation, but disappointingly we were not able to identify any tracer accumulation in OM with any of the supposedly more specific tracers. Conclusion: These negative results are, however, relevant to report as they may save other research groups from conducting the same animal experiments and provide a platform for developing and evaluating other new potential tracers or protocol instead.