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The occurrence of different subtypes of endogenous Cushing’s syndrome (CS) in single individuals is extremely rare. We here present the case of a female patient who was successfully cured from adrenal CS 4 years before being diagnosed with Cushing’s disease (CD). The patient was diagnosed at the age of 50 with ACTH-independent CS and a left-sided adrenal adenoma, in January 2015. After adrenalectomy and histopathological confirmation of a cortisol-producing adrenocortical adenoma, biochemical hypercortisolism and clinical symptoms significantly improved. However, starting from 2018, the patient again developed signs and symptoms of recurrent CS. Subsequent biochemical and radiological workup suggested the presence of ACTH-dependent CS along with a pituitary microadenoma. The patient underwent successful transsphenoidal adenomectomy, and both postoperative adrenal insufficiency and histopathological workup confirmed the diagnosis of CD. Exome sequencing excluded a causative germline mutation but showed somatic mutations of the β-catenin protein gene (CTNNB1) in the adrenal adenoma, and of both the ubiquitin specific peptidase 8 (USP8) and the glucocorticoid receptor (NR3C1) genes in the pituitary adenoma. In conclusion, our case illustrates that both ACTH-independent and ACTH-dependent CS may develop in a single individual even without evidence for a common genetic background.
Aim
Recent advancements in PET technology have brought with it significant improvements in PET performance and image quality. In particular, the extension of the axial field of view of PET systems, and the introduction of semiconductor technology into the PET detector, initially for PET/MR, and more recently available long-field-of-view PET/CT systems (≥ 25 cm) have brought a step change improvement in the sensitivity of PET scanners. Given the requirement to limit paediatric doses, this increase in sensitivity is extremely welcome for the imaging of children and young people. This is even more relevant with PET/MR, where the lack of CT exposures brings further dose reduction benefits to this population. In this short article, we give some details around the benefits around new PET technology including PET/MR and its implications on the EANM paediatric dosage card.
Material and methods
Reflecting on EANM adult guidance on injected activities, and making reference to bed overlap and the concept of MBq.min bed\(^{-1}\) kg\(^{-1}\), we use published data on image quality from PET/MR systems to update the paediatric dosage card for PET/MR and extended axial field of view (≥ 25 cm) PET/CT systems. However, this communication does not cover the expansion of paediatric dosing for the half-body and total-body scanners that have recently come to market.
Results
In analogy to the existing EANM dosage card, new parameters for the EANM paediatric dosage card were developed (class B, baseline value: 10.7 MBq, minimum recommended activity 10 MBq). The recommended administered activities for the systems considered in this communication range from 11 MBq [\(^{18}\)F]FDG for a child with a weight of 3 kg to 149 MBq [\(^{18}\)F]FDG for a paediatric patient weight of 68 kg, assuming a scan of 3 min per bed position. The mean effective dose over all ages (1 year and older) is 2.85 mSv.
Conclusion
With this, recommendations for paediatric dosing are given for systems that have not been considered previously.
Implementierung und Evaluation einer integrierten E-Learning-Plattform für die Nuklearmedizin
(2010)
Zum Thema „Implementierung und Evaluation einer integrierten E-Learning-Plattform für die Nuklearmedizin“ wurde zu Beginn zunächst auf die drei existierenden Lerntheorien - Behaviorismus, Kognitivismus und Konstruktivismus - näher eingegangen, diese miteinander verglichen und in der Folge eine Verbindung zu computerunterstützten Lernprogrammen hergestellt. In Ergänzung dazu wurde der Begriff „E-Learning“ als Kernpunkt des Dissertationsthemas recherchiert und aus verschiedenen Blickwinkeln erörtert. Um feststellen zu können, ob die Einführung eines E-Learning-Angebots im Fachgebiet Nuklearmedizin für die Medizinstudenten des 6. Semesters „gewinnbringend“ ist, wurden für den Kurs „Grundlagen radiologischer Verfahren“ an der Julius-Maximilians-Universität Würzburg 20 Patientenfälle aus der hiesigen Klinik und Poliklinik für Nuklearmedizin erstellt und diese mittels Fallplayer CaseTrain für das Internet generiert. Im Anschluss wurden zur Qualitätskontrolle des Projekts drei ausgewählte Fälle bearbeitet und evaluiert. Es wurden insgesamt 128 Beurteilungen ausgewertet, diese zeigten als wichtigstes Ergebnis, dass sich nach Einschätzung der Evaluierenden ihr Interesse und Wissen am bzw. im Fach Nuklearmedizin nach der Bearbeitung des E-Learning-Kurses signifikant erhöht haben. Aussagekräftig ist auch die Erkenntnis, dass nahezu 100% der Studierenden den Einsatz von computerunterstützten Lernmedien für das Humanmedizinstudium generell für sinnvoll erachten, nur 3% der Befragten eine künftige Benutzung des Programms ablehnten und die Benotung in Bezug auf Fallinhalt und Softwarebedienung überdurchschnittlich gut ausfiel. Aus diesem Grund erscheint es nach Ansicht der Verfasserin sinnvoll, elektronisches Lernen mit der Präsenzlehre im Sinne des „Blended Learning“ zu kombinieren. Zu diesem Zweck wird der Kurs „NUKlearn“ über die Plattform der Virtuellen Hochschule Bayern künftig öffentlich angeboten.
Ziel: Im Mittelpunkt dieser prospektiven Studie steht die Neubestimmung eines geschlechtspezifischen Referenzbereiches für Calcitonin-Konzentrationen, sowohl basal als auch nach Stimulation mit Pentagastrin bzw. Calcium unter Verwendung eines vollautomatischen Assays (Analyseautomat IMMULITE®2000). Aufgrund des gewählten Studiendesigns ist es möglich, die Wertigkeit des etablierten Pentagastrin-Stimulationstests im Vergleich zu einem alternativen Calcium-Stimulationstest zu beurteilen. Methodik: Insgesamt wurden 50 schilddrüsengesunde, nichtrauchende Versuchspersonen (davon 25 weiblich) im Alter von 20 bis 60 Jahren (Mittelwert: 33 Jahre) in die Studie eingeschlossen. Im Vorfeld wurde bei jedem Probanden mittels sonographischer und labortechnischer Untersuchungen (fT3, FT4, TSH, TPO-Antikörper, TG-Antikörper) das Vorliegen krankhafter Veränderungen der Schilddrüse ausgeschlossen. Um einen intraindividuellen Vergleich der intravenösen Stimulationsverfahren zu ermöglichen, erfolgten die Stimulationsversuche unter gleichen Bedingungen (Nahrungskarenz >4h) in einem zeitlichen Abstand von mehreren Wochen. Die Anzahl der Probanden, die an beiden Versuchen teilnahmen, lag bei 42 (davon 18 Frauen). Die Durchführung des Pentagastrin-Tests erfolgte nach dem in unserer Klinik etablierten Protokoll: 0,5 μg Pentagastrin/ kg Körpergewicht Injektion innerhalb von 10 sec.. Die Dosierung des Stimulans Calcium richtete sich nach Angaben der Literatur. Die Stimulation mit Calcium wurde mit Calciumgluconatlösung durchgeführt (2,5 mg Calcium/kg Körpergewicht, mit einer Injektionsgeschwindigkeit von etwa 10ml/min). Vor der Stimulation wurde jeweils der basale Calcitoninspiegel bestimmt. Weitere Blutabnahmen erfolgten direkt im Anschluss an die Injektion sowie 2, 5 und 15 Minuten nach Injektionsende. Sämtliche Calcitoninkonzentrationen wurden mit Hilfe eines Festphasen, Enzym-markierten, Sandwich, immunometrischen Chemilunineszenz Assay (IMMULITE®2000 Calcitonin) bestimmt. Ergebnisse Bei der Betrachtung der 95. Perzentile des basalen Calcitoninspiegels zeigte sich kein deutlicher geschlechtspezifischer Unterschied (95. Perzentile: Männer: 5,0 pg/ml vs. Frauen: 5,7 pg/ml; Mittelwert: Männer: 2,6±1,3 pg/ml vs. Frauen 1,6±1,3 pg/ml). Bei den Stimulationsverfahren hingegen lagen die Calcitoninkonzentrationen in der Gruppe der Männer im Vergleich zur Gruppe der Frauen jeweils signifikant höher (Pentagastrin-Test: p=0,001; Calcium-Test: p=0,004; Mann-Whitney Test). In beiden Testverfahren wurde der Calcitonin Peak nach 2 bis 5 Minuten erreicht. Bei der Gegenüberstellung des Pentagastrin-Tests und des Calcium-Tests bewirkte letzterer den größeren Calcitoninanstieg (Männer: p<0,001, Frauen: p<0,001). Im Einzelnen lag der Wert der 95. Perzentile – zum Zeitpunkt der 2-Minuten-Messung - für Männer im Pentagastrin-Test bei 37,8 pg/ml (Frauen: 26,2 pg/ml) und im Calcium Test bei 95,4 pg/ml (Frauen: 90,2 pg/ml). Die Daten zeigten keinen Anhalt für einen Einfluss von Alter oder Gewicht. Schlussfolgerung Die mit Hilfe eines verbreiteten Analyseautomaten ermittelten geschlechtsspezifischen Referenzbereiche für Calcitonin liegen unterhalb der bisherigen für andere Messverfahren erarbeiteten Angaben. Bei einem schilddrüsengesunden Kollektiv bewirkte die Stimulation mit Calcium im Vergleich zu Pentagastrin einen stärkeren Calcitoninanstieg.
One of the major health consequences of the Chernobyl Nuclear Power Plant accident in 1986 was a dramatic increase in incidence of thyroid cancer among those who were aged less than 18 years at the time of the accident. This increase has been directly linked in several analytic epidemiological studies to iodine-131 (I-131) thyroid doses received from the accident. However, there remains limited understanding of factors that modify the I-131-related risk. Focusing on post-Chernobyl pediatric thyroid cancer in Belarus, we reviewed evidence of the effects of radiation, thyroid screening, and iodine deficiency on regional differences in incidence rates of thyroid cancer. We also reviewed current evidence on content of nitrate in groundwater and thyroid cancer risk drawing attention to high levels of nitrates in open well water in several contaminated regions of Belarus, i.e. Gomel and Brest, related to the usage of nitrogen fertilizers. In this hypothesis generating study, based on ecological data and biological plausibility, we suggest that nitrate pollution may modify the radiation-related risk of thyroid cancer contributing to regional differences in rates of pediatric thyroid cancer in Belarus. Analytic epidemiological studies designed to evaluate joint effect of nitrate content in groundwater and radiation present a promising avenue of research and may provide useful insights into etiology of thyroid cancer.
The incidence of differentiated thyroid cancer (DTC) is steadily increasing globally. Epidemiologists usually explain this global upsurge as the result of new diagnostic modalities, screening and overdiagnosis as well as results of lifestyle changes including obesity and comorbidity. However, there is evidence that there is a real increase of DTC incidence worldwide in all age groups. Here, we review studies on pediatric DTC after nuclear accidents in Belarus after Chernobyl and Japan after Fukushima as compared to cohorts without radiation exposure of those two countries. According to the Chernobyl data, radiation-induced DTC may be characterized by a lag time of 4–5 years until detection, a higher incidence in boys, in children of youngest age, extrathyroidal extension and distant metastases. Radiation doses to the thyroid were considerably lower by appr. two orders of magnitude in children and adolescents exposed to Fukushima as compared to Chernobyl. In DTC patients detected after Fukushima by population-based screening, most of those characteristics were not reported, which can be taken as proof against the hypothesis, that radiation is the (main) cause of those tumors. However, roughly 80% of the Fukushima cases presented with tumor stages higher than microcarcinomas pT1a and 80% with lymph node metastases pN1. Mortality rates in pediatric DTC patients are generally very low, even at higher tumor stages. However, those cases considered to be clinically relevant should be followed-up carefully after treatment because of the risk of recurrencies which is expected to be not negligible. Considering that thyroid doses from the Fukushima accident were quite small, it makes sense to assess the role of other environmental and lifestyle-related factors in thyroid carcinogenesis. Well-designed studies with assessment of radiation doses from medical procedures and exposure to confounders/modifiers from the environment as e.g., nitrate are required to quantify their combined effect on thyroid cancer risk.
Purpose
The impact on patients’ health of radiopharmaceuticals in nuclear medicine diagnostics has not until now been evaluated systematically in a European context. Therefore, as part of the EU-funded Project PEDDOSE.NET (www.peddose.net), we review and summarize the current knowledge on biokinetics and dosimetry of commonly used diagnostic radiopharmaceuticals.
Methods
A detailed literature search on published biokinetic and dosimetric data was performed mostly via PubMed (www.ncbi.nlm.nih.gov/pubmed). In principle the criteria for inclusion of data followed the EANM Dosimetry Committee guidance document on good clinical reporting.
Results
Data on dosimetry and biokinetics can be difficult to find, are scattered in various journals and, especially in paediatric nuclear medicine, are very scarce. The data collection and calculation methods vary with respect to the time-points, bladder voiding, dose assessment after the last data point and the way the effective dose was calculated. In many studies the number of subjects included for obtaining biokinetic and dosimetry data was fewer than ten, and some of the biokinetic data were acquired more than 20 years ago.
Conclusion
It would be of interest to generate new data on biokinetics and dosimetry in diagnostic nuclear medicine using state-of-the-art equipment and more uniform dosimetry protocols. For easier public access to dosimetry data for diagnostic radiopharmaceuticals, a database containing these data should be created and maintained.
DNA double strand break (DSB) formation induced by ionizing radiation exposure is indicated by the DSB biomarkers \(\gamma\)-H2AX and 53BP1. Knowledge about DSB foci formation in-vitro after internal irradiation of whole blood samples with radionuclides in solution will help us to gain detailed insights about dose-response relationships in patients after molecular radiotherapy (MRT). Therefore, we studied the induction of radiation-induced co-localizing \(\gamma\)-H2AX and 53BP1 foci as surrogate markers for DSBs in-vitro, and correlated the obtained foci per cell values with the in-vitro absorbed doses to the blood for the two most frequently used radionuclides in MRT (I-131 and Lu-177). This approach led to an in-vitro calibration curve. Overall, 55 blood samples of three healthy volunteers were analyzed. For each experiment several vials containing a mixture of whole blood and radioactive solutions with different concentrations of isotonic NaCl-diluted radionuclides with known activities were prepared. Leukocytes were recovered by density centrifugation after incubation and constant blending for 1 h at 37°C. After ethanol fixation they were subjected to two-color immunofluorescence staining and the average frequencies of the co-localizing \(\gamma\)-H2AX and 53BP1 foci/nucleus were determined using a fluorescence microscope equipped with a red/green double band pass filter. The exact activity was determined in parallel in each blood sample by calibrated germanium detector measurements. The absorbed dose rates to the blood per nuclear disintegrations occurring in 1 ml of blood were calculated for both isotopes by a Monte Carlo simulation. The measured blood doses in our samples ranged from 6 to 95 mGy. A linear relationship was found between the number of DSB-marking foci/nucleus and the absorbed dose to the blood for both radionuclides studied. There were only minor nuclide-specific intra-and inter-subject deviations.
Background: The American Thyroid Association (ATA) uses criteria to assess the risk for persistent disease in differentiated thyroid carcinoma (DTC) after radioiodine therapy (RAI). There are no data available showing that this classification can be adopted unadjusted by Germany. Aim: The aim of our study is to investigate whether the ATA classification can be applied to a German population for short-term prognosis. Furthermore, we investigated the influence of an age cutoff value. Methods: We retrospectively analyzed 121 patients who were referred to our tertiary referral center. Patients were classified into risk categories, and the therapy response was determined according to ATA. Results: A total of 73/83 (88%) ATA low-risk patients and 12/19 (63%) intermediate-risk patients showed an excellent response; 2/19 (11%) high-risk patients had a biochemical, and 6 (31%) had a structural incomplete response. Of all 39 patients ≥55 years, 84% had an excellent response. Using a cut off of 50 years, 50/62 (81%) of the older patients showed an excellent response. Conclusion: The ATA risk classification is able to estimate the response to RAI therapy in a German population. A shift from 55 to 50 years as an age cutoff value does not result in any relevant change in the treatment response.
Objectives. This study is aimed at investigating the impact of frame numbers in preclinical electrocardiogram- (ECG-) gated \(^{18}\)F-fluorodeoxyglucose (\(^{18}\)F-FDG) positron emission tomography (PET) on systolic and diastolic left ventricular (LV) parameters in rats. Methods. \(^{18}\)F-FDG PET imaging using a dedicated small animal PET system with list mode data acquisition and continuous ECG recording was performed in diabetic and control rats. The list-mode data was sorted and reconstructed with different numbers of frames (4, 8, 12, and 16) per cardiac cycle into tomographic images. Using an automatic ventricular edge detection software, left ventricular (LV) functional parameters, including ejection fraction (EF), end-diastolic (EDV), and end-systolic volume (ESV), were calculated. Diastolic variables (time to peak filling (TPF), first third mean filling rate (1/3 FR), and peak filling rate (PFR)) were also assessed. Results. Significant differences in multiple parameters were observed among the reconstructions with different frames per cardiac cycle. EDV significantly increased by numbers of frames (353.8 & PLUSMN; 57.7 mu l*, 380.8 & PLUSMN; 57.2 mu l*, 398.0 & PLUSMN; 63.1 mu l*, and 444.8 & PLUSMN; 75.3 mu l at 4, 8, 12, and 16 frames, respectively; *P < 0.0001 vs. 16 frames), while systolic (EF) and diastolic (TPF, 1/3 FR and PFR) parameters were not significantly different between 12 and 16 frames. In addition, significant differences between diabetic and control animals in 1/3 FR and PFR in 16 frames per cardiac cycle were observed (P < 0.005), but not for 4, 8, and 12 frames. Conclusions. Using ECG-gated PET in rats, measurements of cardiac function are significantly affected by the frames per cardiac cycle. Therefore, if you are going to compare those functional parameters, a consistent number of frames should be used.
DD is a cardiac disturbance, which has gained increasing importance in recent years due to its important role in different cardiac disease and cardiomyopathies including ischemic cardiomyopathy, arterial hypertension and diabetic cardiomyopathy.
ECG-gated 18F-FDG PET is an imaging technique, that can distinguish between districts of myocardial viability and myocardial scars and further provides information of great interest on the efficacy of experimental approaches designed to improve the cardiac function and/or myocardial metabolism in experimental small animal models. However, ECG-gated 18F-FDG PET is a technique whose feasibility in the assessment of the LV diastolic function in small animals has not been a subject of study.
In this thesis, the ability of the ECG-gated 18F-FDG PET for the assessment of both the systolic and diastolic function in eight control rats and in seven ZDF rats, which are an experimental animal model mimicking T2DM conditions and diabetic related complications in humans including DCM, has been investigated The ECG-gated 18F-FDG PET imaging was performed under hyperinsulinemic-euglycemic clamping and the data were stored in list mode files and retrospectively reconstructed. The systolic and diastolic parameters were achieved from the time/volume and the time/filling curve calculated from the software HFV. Additionally, the influence of the number of gates per cardiac cycle on the LV volumes and function parameters has been studied.
Hyperinsulinemic-euglycemic clamp procedure and blood glucose measurement did confirm the development of a manifest diabetes in the ZDF rats at the timepoint of the experiments.
Regarding the systolic parameters, no significant difference could be detected between the ZDF and ZL rats. The values for the CO were similar in both groups, which demonstrates a similar LV systolic function in the ZDF and the ZL rats at the age of 13 weeks. Values for the systolic parameters are in good line with previous PET, MRI and cardiac catheterization-based studies in diabetic rats.
The main finding of this study was that by using in vivo ECG-gated 18F-FDG PET and the software HFV, reliable diastolic parameters could be calculated. Moreover, it was possible to detect the presence of a mild impaired diastolic filling in the ZDF rats in absence of any systolic alteration. This impaired diastolic function in an early stage of diabetes could also be detected by other investigators, who used echocardiography or cardiac catheterization. Therefore, this is the first study showing, that the assessment of the diastolic function in rats can be carried out by ECG-gated 18F-FDG PET imaging.
In conclusion, additionally to calculating LV volumes and LV EF, ECG-gated 18F-FDG PET can evaluate the diastolic function of healthy and diabetic rats and is able to detect a DD in ZDF rats.
Development of predictable in vitro tumor models is a challenging task due to the enormous complexity of tumors in vivo. The closer the resemblance of these models to human tumor characteristics, the more suitable they are for drug-development and –testing. In the present study, we generated a complex 3D lung tumor test system based on acellular rat lungs. A decellularization protocol was established preserving the architecture, important ECM components and the basement membrane of the lung. Human lung tumor cells cultured on the scaffold formed cluster and exhibited an up-regulation of the carcinoma-associated marker mucin1 as well as a reduced proliferation rate compared to respective 2D culture. Additionally, employing functional imaging with 2-deoxy-2-[\(^{18}\)F]fluoro-D-glucose positron emission tomography (FDG-PET) these tumor cell cluster could be detected and tracked over time. This approach allowed monitoring of a targeted tyrosine kinase inhibitor treatment in the in vitro lung tumor model non-destructively. Surprisingly, FDG-PET assessment of single tumor cell cluster on the same scaffold exhibited differences in their response to therapy, indicating heterogeneity in the lung tumor model. In conclusion, our complex lung tumor test system features important characteristics of tumors and its microenvironment and allows monitoring of tumor growth and -metabolism in combination with functional imaging. In longitudinal studies, new therapeutic approaches and their long-term effects can be evaluated to adapt treatment regimes in future.
Whole-Body [\(^{18}\)F]FDG PET/CT Can Alter Diagnosis in Patients with Suspected Rheumatic Disease
(2021)
The 2-deoxy-d-[\(^{18}\)F]fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) is widely utilized to assess the vascular and articular inflammatory burden of patients with a suspected diagnosis of rheumatic disease. We aimed to elucidate the impact of [\(^{18}\)F]FDG PET/CT on change in initially suspected diagnosis in patients at the time of the scan. Thirty-four patients, who had undergone [\(^{18}\)F]FDG PET/CT, were enrolled and the initially suspected diagnosis prior to [18F]FDG PET/CT was compared to the final diagnosis. In addition, a semi-quantitative analysis including vessel wall-to-liver (VLR) and joint-to-liver (JLR) ratios was also conducted. Prior to [\(^{18}\)F]FDG PET/CT, 22/34 (64.7%) of patients did not have an established diagnosis, whereas in 7/34 (20.6%), polymyalgia rheumatica (PMR) was suspected, and in 5/34 (14.7%), giant cell arteritis (GCA) was suspected by the referring rheumatologists. After [\(^{18}\)F]FDG PET/CT, the diagnosis was GCA in 19/34 (55.9%), combined GCA and PMR (GCA + PMR) in 9/34 (26.5%) and PMR in the remaining 6/34 (17.6%). As such, [\(^{18}\)F]FDG PET/CT altered suspected diagnosis in 28/34 (82.4%), including in all unclear cases. VLR of patients whose final diagnosis was GCA tended to be significantly higher when compared to VLR in PMR (GCA, 1.01 ± 0.08 (95%CI, 0.95–1.1) vs. PMR, 0.92 ± 0.1 (95%CI, 0.85–0.99), p = 0.07), but not when compared to PMR + GCA (1.04 ± 0.14 (95%CI, 0.95–1.13), p = 1). JLR of individuals finally diagnosed with PMR (0.94 ± 0.16, (95%CI, 0.83–1.06)), however, was significantly increased relative to JLR in GCA (0.58 ± 0.04 (95%CI, 0.55–0.61)) and GCA + PMR (0.64 ± 0.09 (95%CI, 0.57–0.71); p < 0.0001, respectively). In individuals with a suspected diagnosis of rheumatic disease, an inflammatory-directed [\(^{18}\)F]FDG PET/CT can alter diagnosis in the majority of the cases, particularly in subjects who were referred because of diagnostic uncertainty. Semi-quantitative assessment may be helpful in establishing a final diagnosis of PMR, supporting the notion that a quantitative whole-body read-out may be useful in unclear cases.
The use of prostate-specific membrane antigen targeted PET imaging for the evaluation of prostate cancer has increased significantly in the last couple of decades. When evaluating these imaging findings based on the PSMA reporting and data system version 1.0, which categorize lesions based on their likelihood of prostate cancer involvement, PSMA-RADS-3A lesions are commonly seen, which are indeterminate for the presence of disease. A total of 28 patients with 171 PSMA-RADS-3A lesions on \(^{18}\)F-DCFPyL PET/CT scans from June 2016 to May 2017 who had follow-up cross-sectional imaging over time were included in this study. The PSA levels of patients with PSMA-RADS-3A lesions were categorized into four groups, 0–0.2, 0.2–1, 1–2, and >2 ng/mL. The pre-operative Gleason score of these patients was categorized into two groups, Gleason score < 7 or ≥7. The median age for these patients was 72.5 years (range 59–81). The median PSA value for patients with positive lesions was significantly higher than those with negative lesions (5.8 ng/mL vs. 0.2 ng/mL, p < 0.0001). The lesion positivity rate was significantly higher in patients with PSA > 1 ng/mL (18.2% vs. 81.9%, p < 0.001). On ROC analysis, the highest classification accuracy was seen at PSA ≥ 0.6 ng/mL of 80.12% (95% CI = 73.69–86.16%), and the area under the curve was 71.32% (95% CI = 61.9–80.7%, p < 0.0001). A total of 96.4% (108/112) of patients with positive lesions and 86.4% (51/59) of patients with negative lesions had a PSMA-RADS-4/5 lymph node on the initial \(^{18}\)F-DCFPyL PET/CT scan (p = 0.02). In patients with a Gleason score ≥ 7, the presence of positive PSMA-RADS-3A lesions was higher, compared to negative PSMA-RADS-3A lesions (p = 0.049). Higher PSA levels in patients with PSMA-RADS-3A lesions can point towards the presence of true positivity. PSA levels may be considered in deciding whether to call an indeterminate lesion on PSMA PET.
Purpose
A neuropathological hallmark of Alzheimer's disease (AD) is the presence of amyloid-β (Aβ) plaques in the brain, which are observed in a significant number of cognitively normal, older adults as well. In AD, butyrylcholinesterase (BChE) becomes associated with A\(_{β}\) aggregates, making it a promising target for imaging probes to support diagnosis of AD. In this study, we present the synthesis, radiochemistry, in vitro and preliminary ex and in vivo investigations of a selective, reversible BChE inhibitor as PET-tracer for evaluation as an AD diagnostic.
Procedures
Radiolabeling of the inhibitor was achieved by fluorination of a respective tosylated precursor using K[\(^{18}\)F]. IC\(_{50}\) values of the fluorinated compound were obtained in a colorimetric assay using recombinant, human (h) BChE. Dissociation constants were determined by measuring hBChE activity in the presence of different concentrations of inhibitor.
Results
Radiofluorination of the tosylate precursor gave the desired radiotracer in an average radiochemical yield of 20 ± 3 %. Identity and > 95.5 % radiochemical purity were confirmed by HPLC and TLC autoradiography. The inhibitory potency determined in Ellman's assay gave an IC\(_{50}\) value of 118.3 ± 19.6 nM. Dissociation constants measured in kinetic experiments revealed lower affinity of the inhibitor for binding to the acylated enzyme (K2 = 68.0 nM) in comparison to the free enzyme (K\(_{1}\) = 32.9 nM).
Conclusions
The reversibly acting, selective radiotracer is synthetically easily accessible and retains promising activity and binding potential on hBChE. Radiosynthesis with \(^{18}\)F labeling of tosylates was feasible in a reasonable time frame and good radiochemical yield.
The enzyme butyrylcholinesterase (BChE) represents a promising target for imaging probes to potentially enable early diagnosis of neurodegenerative diseases like Alzheimer's disease (AD) and to monitor disease progression in some forms of cancer. In this study, we present the design, facile synthesis, in vitro and preliminary ex vivo and in vivo evaluation of a morpholine‐based, selective inhibitor of human BChE as a positron emission tomography (PET) tracer with a pseudo‐irreversible binding mode. We demonstrate a novel protecting group strategy for 18F radiolabeling of carbamate precursors and show that the inhibitory potency as well as kinetic properties of our unlabeled reference compound were retained in comparison to the parent compound. In particular, the prolonged duration of enzyme inhibition of such a morpholinocarbamate motivated us to design a PET tracer, possibly enabling a precise mapping of BChE distribution.
Purpose
FAPI ligands (fibroblast activation protein inhibitor), a novel class of radiotracers for PET/CT imaging, demonstrated in previous studies rapid and high tumor uptake. The purpose of this study is the head-to-head intra-individual comparison of \(^{68}\)Ga-FAPI versus standard-of-care \(^{18}\)F-FDG in PET/CT in organ biodistribution and tumor uptake in patients with various cancers.
Material and Methods
This international retrospective multicenter analysis included PET/CT data from 71 patients from 6 centers who underwent both \(^{68}\)Ga-FAPI and \(^{18}\)F-FDG PET/CT within a median time interval of 10 days (range 1–89 days). Volumes of interest (VOIs) were manually drawn in normal organs and tumor lesions to quantify tracer uptake by SUVmax and SUVmean. Furthermore, tumor-to-background ratios (TBR) were generated (SUVmax tumor/ SUVmax organ).
Results
A total of 71 patients were studied of, which 28 were female and 43 male (median age 60). In 41 of 71 patients, the primary tumor was present. Forty-three of 71 patients exhibited 162 metastatic lesions. \(^{68}\)Ga-FAPI uptake in primary tumors and metastases was comparable to 18F-FDG in most cases. The SUVmax was significantly lower for \(^{68}\)Ga-FAPI than \(^{18}\)F-FDG in background tissues such as the brain, oral mucosa, myocardium, blood pool, liver, pancreas, and colon. Thus, \(^{68}\)Ga-FAPI TBRs were significantly higher than 18F-FDG TBRs in some sites, including liver and bone metastases.
Conclusion
Quantitative tumor uptake is comparable between \(^{68}\)Ga-FAPI and \(^{18}\)F-FDG, but lower background uptake in most normal organs results in equal or higher TBRs for \(^{68}\)Ga-FAPI. Thus, \(^{68}\)Ga-FAPI PET/CT may yield improved diagnostic information in various cancers and especially in tumor locations with high physiological \(^{18}\)F-FDG uptake.
Background: Dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibition offers an attractive therapeutic strategy in anaplastic large cell lymphoma depending on oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) signaling. We tested the efficacy of a novel dual PI3K/mTOR inhibitor, NVP-BGT226 (BGT226), in two anaplastic large cell lymphoma cell lines in vitro and in vivo and performed an early response evaluation with positron emission tomography (PET) imaging using the standard tracer, 2-deoxy-2-[F-18] fluoro-D-glucose (FDG) and the thymidine analog, 3'-deoxy-3'-[F-18] fluorothymidine (FLT).
Methods: The biological effects of BGT226 were determined in vitro in the NPM-ALK positive cell lines SU-DHL-1 and Karpas299 by 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, propidium iodide staining, and biochemical analysis of PI3K and mTOR downstream signaling. FDG-PET and FLT-PET were performed in immunodeficient mice bearing either SU-DHL-1 or Karpas299 xenografts at baseline and 7 days after initiation of treatment with BGT226. Lymphomas were removed for immunohistochemical analysis of proliferation and apoptosis to correlate PET findings with in vivo treatment effects.
Results: SU-DHL-1 cells showed sensitivity to BGT226 in vitro, with cell cycle arrest in G0/G1 phase and an IC50 in the low nanomolar range, in contrast with Karpas299 cells, which were mainly resistant to BGT226. In vivo, both FDG-PET and FLT-PET discriminated sensitive from resistant lymphoma, as indicated by a significant reduction of tumor-to-background ratios on day 7 in treated SU-DHL-1 lymphoma-bearing animals compared with the control group, but not in animals with Karpas299 xenografts. Imaging results correlated with a marked decrease in the proliferation marker Ki67, and a slight increase in the apoptotic marker, cleaved caspase 3, as revealed by immunostaining of explanted lymphoma tissue.
Conclusion: Dual PI3K/mTOR inhibition using BGT226 is effective in ALK-positive anaplastic large cell lymphoma and can be monitored with both FDG-PET and FLT-PET early on in the course of therapy.
Background
Fast and accurate T1ρ mapping in myocardium is still a major challenge, particularly in small animal models. The complex sequence design owing to electrocardiogram and respiratory gating leads to quantification errors in in vivo experiments, due to variations of the T\(_{1p}\) relaxation pathway. In this study, we present an improved quantification method for T\(_{1p}\) using a newly derived formalism of a T\(_{1p}\)\(^{*}\) relaxation pathway.
Methods
The new signal equation was derived by solving a recursion problem for spin-lock prepared fast gradient echo readouts. Based on Bloch simulations, we compared quantification errors using the common monoexponential model and our corrected model. The method was validated in phantom experiments and tested in vivo for myocardial T\(_{1p}\) mapping in mice. Here, the impact of the breath dependent spin recovery time T\(_{rec}\) on the quantification results was examined in detail.
Results
Simulations indicate that a correction is necessary, since systematically underestimated values are measured under in vivo conditions. In the phantom study, the mean quantification error could be reduced from − 7.4% to − 0.97%. In vivo, a correlation of uncorrected T\(_{1p}\) with the respiratory cycle was observed. Using the newly derived correction method, this correlation was significantly reduced from r = 0.708 (p < 0.001) to r = 0.204 and the standard deviation of left ventricular T\(_{1p}\) values in different animals was reduced by at least 39%.
Conclusion
The suggested quantification formalism enables fast and precise myocardial T\(_{1p}\) quantification for small animals during free breathing and can improve the comparability of study results. Our new technique offers a reasonable tool for assessing myocardial diseases, since pathologies that cause a change in heart or breathing rates do not lead to systematic misinterpretations. Besides, the derived signal equation can be used for sequence optimization or for subsequent correction of prior study results.
Purpose
T\(_{1P}\) dispersion quantification can potentially be used as a cardiac magnetic resonance index for sensitive detection of myocardial fibrosis without the need of contrast agents. However, dispersion quantification is still a major challenge, because T\(_{1P}\) mapping for different spin lock amplitudes is a very time consuming process. This study aims to develop a fast and accurate T\(_{1P}\) mapping sequence, which paves the way to cardiac T1ρ dispersion quantification within the limited measurement time of an in vivo study in small animals.
Methods
A radial spin lock sequence was developed using a Bloch simulation-optimized sampling pattern and a view-sharing method for image reconstruction. For validation, phantom measurements with a conventional sampling pattern and a gold standard sequence were compared to examine T\(_{1P}\) quantification accuracy. The in vivo validation of T\(_{1P}\) mapping was performed in N = 10 mice and in a reproduction study in a single animal, in which ten maps were acquired in direct succession. Finally, the feasibility of myocardial dispersion quantification was tested in one animal.
Results
The Bloch simulation-based sampling shows considerably higher image quality as well as improved T\(_{1P}\) quantification accuracy (+ 56%) and precision (+ 49%) compared to conventional sampling. Compared to the gold standard sequence, a mean deviation of - 0.46 ± 1.84% was observed. The in vivo measurements proved high reproducibility of myocardial T\(_{1P}\) mapping. The mean T\(_{1P}\) in the left ventricle was 39.5 ± 1.2 ms for different animals and the maximum deviation was 2.1% in the successive measurements. The myocardial T\(_{1P}\) dispersion slope, which was measured for the first time in one animal, could be determined to be 4.76 ± 0.23 ms/kHz.
Conclusion
This new and fast T\(_{1P}\) quantification technique enables high-resolution myocardial T\(_{1P}\) mapping and even dispersion quantification within the limited time of an in vivo study and could, therefore, be a reliable tool for improved tissue characterization.
Purpose
As α-emitters for radiopharmaceutical therapies are administered systemically by intravenous injection, blood will be irradiated by α-particles that induce clustered DNA double-strand breaks (DSBs). Here, we investigated the induction and repair of DSB damage in peripheral blood mononuclear cells (PBMCs) as a function of the absorbed dose to the blood following internal ex vivo irradiation with [\(^{223}\)Ra]RaCl2.
Methods
Blood samples of ten volunteers were irradiated by adding [\(^{223}\)Ra]RaCl2 solution with different activity concentrations resulting in absorbed doses to the blood of 3 mGy, 25 mGy, 50 mGy and 100 mGy. PBMCs were isolated, divided in three parts and either fixed directly (d-samples) or after 4 h or 24 h culture. After immunostaining, the induced γ-H2AX α-tracks were counted. The time-dependent decrease in α-track frequency was described with a model assuming a repair rate R and a fraction of non-repairable damage Q.
Results
For 25 mGy, 50 mGy and 100 mGy, the numbers of α-tracks were significantly increased compared to baseline at all time points. Compared to the corresponding d-samples, the α-track frequency decreased significantly after 4 h and after 24 h. The repair rates R were (0.24 ± 0.05) h−1 for 25 mGy, (0.16 ± 0.04) h−1 for 50 mGy and (0.13 ± 0.02) h−1 for 100 mGy, suggesting faster repair at lower absorbed doses, while Q-values were similar.
Conclusion
The results obtained suggest that induction and repair of the DSB damage depend on the absorbed dose to the blood. Repair rates were similar to what has been observed for irradiation with low linear energy transfer.
Introduction
In men with metastatic castration-resistant prostate cancer (mCRPC) scheduled for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), biochemical response is assessed based on repeated measurements of prostate-specific antigen (PSA) levels. We aimed to determine overall survival (OS) in patients experiencing sustained PSA increase, decrease, or fluctuations during therapy.
Materials and methods
In this bicentric study, we included 176 mCRPC patients treated with PSMA-directed RLT. PSA levels were determined using blood samples prior to the first RLT and on the admission days for the following cycles. We calculated relative changes in PSA levels compared to baseline. Kaplan–Meier curves as well as log-rank test were used to compare OS of different subgroups, including patients with sustained PSA increase, decrease, or fluctuations (defined as change after initial decrease or increase after the first cycle).
Results
Sixty-one out of one hundred seventy-six (34.7%) patients showed a sustained increase and 86/176 (48.8%) a sustained decrease in PSA levels. PSA fluctuations were observed in the remaining 29/176 (16.5%). In this subgroup, 22/29 experienced initial PSA decrease followed by an increase (7/29, initial increase followed by a decrease). Median OS of patients with sustained decrease in PSA levels was significantly longer when compared to patients with sustained increase of PSA levels (19 vs. 8 months; HR 0.35, 95% CI 0.22–0.56; P < 0.001). Patients with PSA fluctuations showed a significantly longer median OS compared to patients with sustained increase of PSA levels (18 vs. 8 months; HR 0.49, 95% CI 0.30–0.80; P < 0.01), but no significant difference relative to men with sustained PSA decrease (18 vs. 19 months; HR 1.4, 95% CI 0.78–2.49; P = 0.20). In addition, in men experiencing PSA fluctuations, median OS did not differ significantly between patients with initial decrease or initial increase of tumor marker levels (16 vs. 18 months; HR 1.2, 95% CI 0.38–4.05; P = 0.68).
Conclusion
Initial increase or decrease of PSA levels is sustained in the majority of patients undergoing RLT. Sustained PSA decrease was linked to prolonged survival and men with PSA fluctuations under treatment experienced comparable survival benefits. As such, transient tumor marker oscillations under RLT should rather not lead to treatment discontinuation, especially in the absence of radiological progression.
(1) Background: Prostate-specific membrane antigen (PSMA)-derived tumour volume (PSMA-TV) and total lesion PSMA (TL-PSMA) from PSMA PET/CT scans are promising biomarkers for assessing treatment response in prostate cancer (PCa). Currently, it is unclear whether different software tools for assessing PSMA-TV and TL-PSMA produce comparable results. (2) Methods: \(^{68}\)Ga-PSMA PET/CT scans from n = 21 patients with castration-resistant PCa (CRPC) receiving chemotherapy were identified from our single-centre database. PSMA-TV and TL-PSMA were calculated with Syngo.via (Siemens) as well as the freely available Beth Israel plugin for FIJI (Fiji Is Just ImageJ) before and after chemotherapy. While statistical comparability was illustrated and quantified via Bland-Altman diagrams, the clinical agreement was estimated by matching PSMA-TV, TL-PSMA and relative changes of both variables during chemotherapy with changes in serum PSA (ΔPSA) and PERCIST (Positron Emission Response Criteria in Solid Tumors). (3) Results: Comparing absolute PSMA-TV and TL-PSMA as well as Bland–Altman plotting revealed a good statistical comparability of both software algorithms. For clinical agreement, classifying therapy response did not differ between PSMA-TV and TL-PSMA for both software solutions and showed highly positive correlations with BR. (4) Conclusions: due to the high levels of statistical and clinical agreement in our CRPC patient cohort undergoing taxane chemotherapy, comparing PSMA-TV and TL-PSMA determined by Syngo.via and FIJI appears feasible.
Simple Summary
The calculation of PSMA-positive tumor volume (PSMA-TV) of the whole body from PSMA PET scans for response evaluation remains a time-consuming procedure. We hypothesized that it may be possible to quantify changes in PSMA-TV by considering only a limited number of representative tumor lesions. Changes in the whole-body PSMA-TV of 65 patients were comparable to the changes in PSMA-TV after including only the ten largest lesions. Moreover, changes in PSMA-TV correlated well with changes in PSA levels, as did the changes in PSMA-TV with the reduced number of lesions. We conclude that a response assessment using PSMA-TV with a reduced number of lesions is feasible and could lead to a simplified process for evaluating PSMA PET/CT.
Abstract
(1) Background: Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)-derived parameters, such as the commonly used standardized uptake value (SUV) and PSMA-positive tumor volume (PSMA-TV), have been proposed for response assessment in metastatic prostate cancer (PCa) patients. However, the calculation of whole-body PSMA-TV remains a time-consuming procedure. We hypothesized that it may be possible to quantify changes in PSMA-TV by considering only a limited number of representative lesions. (2) Methods: Sixty-five patients classified into different disease stages were assessed by PSMA PET/CT for staging and restaging after therapy. Whole-body PSMA-TV and whole-body SUV\(_{max}\) were calculated. We then repeated this calculation only including the five or ten hottest or largest lesions. The corresponding serum levels of prostate-specific antigen (PSA) were also determined. The derived delta between baseline and follow-up values provided the following parameters: ΔSUV\(_{maxall}\), ΔSUV\(_{max10}\), ΔSUV\(_{max5}\), ΔPSMA-TV\(_{all}\), ΔPSMA-TV\(_{10}\), ΔPSMA-TV\(_{5}\), ΔPSA. Finally, we compared the findings from our whole-body segmentation with the results from our keyhole approach (focusing on a limited number of lesions) and correlated all values with the biochemical response (ΔPSA). (3) Results: Among patients with metastatic hormone-sensitive PCa (mHSPC), none showed a relevant deviation for ΔSUV\(_{max10}\)/ΔSUV\(_{max5}\) or ΔPSMA-TV\(_{10}\)/ΔPSMA-TV\(_{5}\) compared to ΔSUV\(_{maxall}\) and ΔPSMA-TV\(_{all}\). For patients treated with taxanes, up to 6/21 (28.6%) showed clinically relevant deviations between ΔSUV\(_{maxall}\) and ΔSUV\(_{max10}\) or ΔSUV\(_{max5}\), but only up to 2/21 (9.5%) patients showed clinically relevant deviations between ΔPSMA-TV\(_{all}\) and ΔPSMA-TV\(_{10}\) or ΔPSMA-TV\(_{5}\). For patients treated with radioligand therapy (RLT), up to 5/28 (17.9%) showed clinically relevant deviations between ΔSUV\(_{maxall}\) and ΔSUV\(_{max10}\) or ΔSUV\(_{max5}\), but only 1/28 (3.6%) patients showed clinically relevant deviations between ΔPSMA-TV\(_{all}\) and ΔPSMA-TV\(_{10}\) or ΔPSMA-TV\(_{5}\). The highest correlations with ΔPSA were found for ΔPSMA-TV\(_{all}\) (r ≥ 0.59, p ≤ 0.01), followed by ΔPSMA-TV\(_{10}\) (r ≥ 0.57, p ≤ 0.01) and ΔPSMA-TV\(_{5}\) (r ≥ 0.53, p ≤ 0.02) in all cohorts. ΔPSA only correlated with ΔSUV\(_{maxall}\) (r = 0.60, p = 0.02) and with ΔSUV\(_{max10}\) (r = 0.53, p = 0.03) in the mHSPC cohort, as well as with ΔSUV\(_{maxall}\) (r = 0.51, p = 0.01) in the RLT cohort. (4) Conclusion: Response assessment using PSMA-TV with a reduced number of lesions is feasible, and may allow for a simplified evaluation process for PSMA PET/CT.
Simple Summary
Discordant FDG-positive but PSMA-negative (FDG+/PSMA−) metastases constitute a negative prognostic marker of overall survival in patients undergoing PSMA radioligand therapy (RLT). The aim of this analysis was to investigate the prognostic implications of new FDG+/PSMA− lesions, which occur during or after PSMA RLT. In a retrospective bicentric analysis of 32 patients undergoing PSMA RLT and follow-up dual tracer staging with PSMA and FDG PET/CT, FDG+/PSMA− lesions occurred in a limited number of patients. However, the presence of FDG+/PSMA− lesions appears not to have a significant impact on the OS, but further studies are needed to establish the clinical relevance of such lesions.
Abstract
Introduction: Positron emission tomography/computer tomography (PET/CT) targeting the prostate-specific membrane antigen (PSMA) is crucial for the assessment of adequate PSMA expression in patients with metastatic castration-resistant prostate cancer (mCRPC) prior to PSMA radioligand therapy (PSMA RLT). Moreover, initial dual tracer staging using combined PSMA and [\(^{18}\)F]fluorodeoxyglucose (FDG) PET/CT provides relevant information, since discordant FDG-positive but PSMA-negative (FDG+/PSMA−) lesions constitute a negative prognostic marker of overall survival (OS) after PSMA RLT. However, little is known about the prognostic implications of dual tracer imaging for restaging at follow-up. The aim of this analysis was to investigate the prognostic implications of new FDG+/PSMA− lesions during or after PSMA RLT. Methods: This bicentric analysis included 32 patients with mCRPC who underwent both FDG and PSMA PET/CT imaging after two or four cycles of PSMA RLT. Patients with FDG+/PSMA− lesions prior to PSMA RLT were not considered. The presence of FDG+/PSMA− lesions was assessed with follow-up dual tracer imaging of patients after two or four cycles of PSMA RLT. Patients with at least one new FDG+/PSMA− lesion were compared to patients without any FDG+/PSMA− lesions at the respective time points. A log-rank analysis was used to assess the difference in OS between subgroups. Results: After two cycles of PSMA RLT, four of 32 patients (13%) had FDG+/PSMA− metastases. No significant difference in OS was observed (p = 0.807), as compared to patients without FDG+/PSMA− lesions. Follow-up dual tracer imaging after the 4th cycle of PSMA RLT was available in 18 patients. Of these, four patients presented with FDG+/PSMA− findings (n = 2 already after two cycles). After the fourth cycle of PSMA RLT, no significant difference in OS was observed between patients with and without FDG+/PSMA− lesions (p = 0.442). Conclusion: This study shows that FDG+/PSMA− lesions develop in a limited number of patients undergoing PSMA RLT. Further studies are needed to establish the clinical relevance of such lesions.
Background
Radioligand therapy (RLT) with \(^{177}\)Lu-labeled prostate-specific membrane antigen (PSMA) ligands is associated with prolonged overall survival (OS) in patients with advanced, metastatic castration-resistant prostate cancer (mCRPC). A substantial number of patients, however, are prone to treatment failure. We aimed to determine clinical baseline characteristics to predict OS in patients receiving [\(^{177}\)Lu]Lu-PSMA I&T RLT in a long-term follow-up.
Materials and methods
Ninety-two mCRPC patients treated with [\(^{177}\)Lu]Lu-PSMA I&T with a follow-up of at least 18 months were retrospectively identified. Multivariable Cox regression analyses were performed for various baseline characteristics, including laboratory values, Gleason score, age, prior therapies, and time interval between initial diagnosis and first treatment cycle (interval\(_{Diagnosis-RLT}\), per 12 months). Cutoff values for significant predictors were determined using receiver operating characteristic (ROC) analysis. ROC-derived thresholds were then applied to Kaplan–Meier analyses.
Results
Baseline C-reactive protein (CRP; hazard ratio [HR], 1.10, 95% CI 1.02–1.18; P = 0.01), lactate dehydrogenase (LDH; HR, 1.07, 95% CI 1.01–1.11; P = 0.01), aspartate aminotransferase (AST; HR, 1.16, 95% CI 1.06–1.26; P = 0.001), and interval\(_{Diagnosis-RLT}\) (HR, 0.95, 95% CI 0.91–0.99; P = 0.02) were identified as independent prognostic factors for OS. The following respective ROC-based thresholds were determined: CRP, 0.98 mg/dl (area under the curve [AUC], 0.80); LDH, 276.5 U/l (AUC, 0.83); AST, 26.95 U/l (AUC, 0.73); and interval\(_{Diagnosis-RLT}\), 43.5 months (AUC, 0.68; P < 0.01, respectively). Respective Kaplan–Meier analyses demonstrated a significantly longer median OS of patients with lower CRP, lower LDH, and lower AST, as well as prolonged interval\(_{Diagnosis-RLT}\) (P ≤ 0.01, respectively).
Conclusion
In mCRPC patients treated with [\(^{177}\)Lu]Lu-PSMA I&T, baseline CRP, LDH, AST, and time interval until RLT initiation (thereby reflecting a possible indicator for tumor aggressiveness) are independently associated with survival. Our findings are in line with previous findings on [\(^{177}\)Lu]Lu-PSMA-617, and we believe that these clinical baseline characteristics may support the nuclear medicine specialist to identify long-term survivors.
Background
Labelled with lutetium-177, the urea-based small molecules PSMA I&T and PSMA-617 are the two agents most frequently used for radioligand therapy (RLT) in patients with advanced metastatic castration-resistant and prostate-specific membrane antigen (PSMA) expressing prostate cancer (mCRPC). In this matched-pair analysis, we aimed to compare the toxicity and efficacy of both agents for PSMA-directed RLT.
Materials and methods
A total of 110 mCRPC patients from two centres were accrued, 55 individuals treated with [\(^{177}\)Lu]Lu-PSMA I&T, and a matched cohort of 55 patients treated with [\(^{177}\)Lu]Lu-PSMA-617. Matching criteria included age at the first cycle, Gleason score, prostate-specific antigen (PSA) values, and previous taxane-based chemotherapy. Using common terminology criteria for adverse events (CTCAE v. 5.0), toxicity profiles were investigated (including bone marrow and renal toxicity). Overall survival (OS) between both groups was compared.
Results
Toxicity assessment revealed grade III anaemia in a single patient (1.8%) for [\(^{177}\)Lu]Lu-PSMA I&T and five (9.1%) for [\(^{177}\)Lu]Lu-PSMA-617. In addition, one (1.9%) grade III thrombopenia for [\(^{177}\)Lu]Lu-PSMA-617 was recorded. Apart from that, no other grade III/IV toxicities were present. A median OS of 12 months for patients treated with [\(^{177}\)Lu]Lu-PSMA I&T did not differ significantly when compared to patients treated with [\(^{177}\)Lu]Lu-PSMA-617 (median OS, 13 months; P = 0.89).
Conclusion
In this matched-pair analysis of patients receiving one of the two agents most frequently applied for PSMA RLT, the rate of clinically relevant toxicities was low for both compounds. In addition, no relevant differences for OS were observed.
Background
Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is increasingly incorporated in the therapeutic algorithm of patients with metastatic castration-resistant prostate cancer (mCRPC). We aimed to elucidate the predictive performance of early biochemical response for overall survival (OS).
Materials and Methods
In this bicentric analysis, we included 184 mCRPC patients treated with \(^{177}\)Lu-PSMA RLT. Response to treatment was defined as decrease in prostate-specific antigen (PSA) levels 8 weeks after the first cycle of RLT (any decline or >50% according to Prostate Cancer Working Group 3). OS of responders and nonresponders was then compared using Kaplan–Meier curves and log-rank comparison.
Results
A total of 114/184 patients (62.0%) showed any PSA decline (PSA response >50%, 55/184 [29.9%]). For individuals exhibiting a PSA decline >50%, OS of 19 months was significantly longer relative to nonresponders (13 months; hazard ratio of death [HR] = 0.64, 95% confidence interval [95% CI] = 0.44–0.93; p = 0.02). However, the difference was even more pronounced for any PSA decline, with an OS of 19 months in responders, but only 8 months in nonresponders (HR = 0.39, 95% CI = 0.25–0.60; p < 0.001).
Conclusions
In mCRPC patients scheduled for RLT, early biochemical response was tightly linked to prolonged survival, irrespective of the magnitude of PSA decline. As such, even in patients with PSA decrease of less than 50%, RLT should be continued.
(1) Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) has shown remarkable results in patients with advanced prostate cancer. We aimed to evaluate the toxicity profile of the PSMA ligand [\(^{177}\)Lu]Lu-PSMA I&T. (2) Methods: 49 patients with metastatic, castration-resistant prostate cancer treated with at least three cycles of [\(^{177}\)Lu]Lu-PSMA I&T were evaluated. Prior to and after RLT, we compared leukocytes, hemoglobin, platelet counts, and renal functional parameters (creatinine, eGFR, n = 49; [\(^{99m}\)Tc]-MAG3-derived tubular extraction rate (TER), n = 42). Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and KDIGO Society. To identify predictive factors, we used Spearman's rank correlation coefficient. (3) Results: A substantial fraction of the patients already showed impaired renal function and reduced leukocyte counts at baseline. Under RLT, 11/49 (22%) patients presented with nephrotoxicity CTCAE I or II according to creatinine, but 33/49 (67%) according to eGFR. Only 5/42 (13%) showed reduced TER, defined as <70% of the age-adjusted mean normal values. Of all renal functional parameters, absolute changes of only 2% were recorded. CTCAE-based re-categorization was infrequent, with creatinine worsening from I to II in 2/49 (4.1%; GFR, 1/49 (2%)). Similar results were recorded for KDIGO (G2 to G3a, 1/49 (2%); G3a to G3b, 2/49 (4.1%)). After three cycles, follow-up eGFR correlated negatively with age (r = −0.40, p = 0.005) and the eGFR change with Gleason score (r = −0.35, p < 0.05) at baseline. Leukocytopenia CTCAE II occurred only in 1/49 (2%) (CTCAE I, 20/49 (41%)) and CTCAE I thrombocytopenia in 7/49 (14%), with an absolute decrease of 15.2% and 16.6% for leukocyte and platelet counts. Anemia CTCAE II occurred in 10/49 (20%) (CTCAE I, 36/49 (73%)) with a decrease in hemoglobin of 4.7%. (4) Conclusions: After PSMA-targeted therapy using [\(^{177}\)Lu]Lu-PSMA I&T, no severe (CTCAE III/IV) toxicities occurred, thereby demonstrating that serious adverse renal or hematological events are unlikely to be a frequent phenomenon with this agent.
Das Prostatakarzinom (PCa) stellt derzeit in Deutschland die häufigste Krebserkrankung der männlichen Bevölkerung dar und steht bei den tödlich verlaufenden Malignomen an zweiter Stelle. Aktuell umfasst die Diagnostik immer öfter auch eine molekulare Bildgebung mittels PET/CT und den Tracern [18F]Cholin und [68Ga]PSMA. Letzterer detektiert selektiv das prostataspezifische Membranantigen (PSMA), welches in Prostatakarzinomzellen häufig überexprimiert ist. Das Wachstum von PCa geschieht in der Regel androgenabhängig, wobei sich auch teilweise eine androgenunabhängige Entwicklung findet. Für das bei kastrationsresistenten Karzinomen und fortgeschrittenen Stadien eingesetzte Chemotherapeutikum Docetaxel, werden immer wieder Resistenzentwicklungen beobachtet, wodurch dieses nur unzureichend effektiv ist. Ziel dieser Arbeit war es, die Eignung verschiedener PET-Tracer ([18F]FDG, [18F]Cholin und [68Ga]PSMA) zur Bildgebung androgenabhängiger und -unabhängiger Prostatakarzinomzellen zu testen sowie ihr Potential zur Beurteilung des Therapieansprechens auf Docetaxel zu untersuchen. Weiterhin sollte untersucht werden, ob die [68Ga]PSMA-Retention mit der PSMA-Expression korreliert. Im zweiten Teil wurde ein Zusammenhang zwischen der Expression von PSMA und der Resistenzentwicklung gegen Docetaxel untersucht.
Methoden: Für die in-vitro Experimente wurden die hormonabhängige Zelllinie LNCaP sowie die hormonunabhängige Zelllinie LNCaP C4-2 verwendet. Im zweiten Teil wurden zusätzlich PSMA-negative PC-3 Zellen eingesetzt. Die aufgenommene bzw. gebundene Traceraktivität wurde mittels Gammacounter gemessen. Die Untersuchung der PSMA-Expression erfolgte mit Western-Blot und Durchflusszytometrie. Ein PSMA-Knockdown-System wurde mittels siRNA in LNCaP-Zellen etabliert.
Ergebnisse: Die PSMA-Expression und die Sensitivität gegenüber Docetaxel waren bei LNCaP Zellen tendenziell erhöht gegenüber der LNCaP C4-2 Zelllinie. Nach Docetaxelbehandlung zeigte sich in beiden Zellreihen eine unveränderte PSMA-Expression. Der PSMA-spezifische PET-Tracer zeigte, im Vergleich zu den metabolischen Tracern [18F]FDG und [18F]Cholin, eine nur sehr geringe Retention. Im Vergleich der Zelllinien untereinander nahmen LNCaP C4-2 Zellen ca. 50 % mehr [18F]FDG auf als LNCaP Zellen. Die Aufnahme von [18F]Cholin unterschied sich nicht signifikant. Der Tracer [68Ga]PSMA zeigte eine höhere Bindung an LNCaP Zellen im Vergleich zu LNCaP C4-2 Zellen. In weiteren Versuchen konnte gezeigt werden, dass sowohl [18F]FDG als auch [18F]Cholin, nicht jedoch [68Ga]PSMA in vitro ein Therapieansprechen auf Docetaxel durch verminderte Traceraufnahme in beiden Zelllinien aufzeigen. Es konnte zudem eine direkte Korrelation zwischen der [68Ga]PSMA-Bindung und der PSMA-Expression nachgewiesen werden.
Nach einer siRNA-vermittelten Verminderung der PSMA-Expression in LNCaP Zellen (Knockdown-Zellen) zeigte sich eine deutlich geringere Sensitivität für Docetaxel. Gleichzeitig war jedoch die Docetaxelsensitivität von PSMA-negativen PC-3 Zellen höher als die von LNCaP Knockdown-Zellen.
Schlussfolgerung: Insgesamt zeigten unsere Untersuchungen, dass sich die PET-Tracer [18F]FDG und [68Ga]PSMA zur Unterscheidung des androgenabhängigen Zellmodells vom androgenunabhängigen Modell eignen. Außerdem ermöglicht der [68Ga]PSMA-Tracer eine Einschätzung der PSMA-Expression. Die Tracer [18F]FDG und [18F]Cholin eignen sich in vitro für die Beurteilung des Therapieansprechens einer Docetaxeltherapie, [68Ga]PSMA dagegen nicht. Die PSMA-Expression scheint ein entscheidender, aber nicht alleinstehender Faktor für die Sensitivität von LNCaP Zellen gegenüber Docetaxel zu sein. Es scheinen hierbei allerdings eher der Verlust von PSMA, wie im Knockdown-Modell induziert, sowie bislang unbekannte Faktoren eine wichtige Rolle zu spielen.
Die autoimmune Thyreoiditis nach Hashimoto stellt aktuell eine der häufigsten Autoimmunerkrankungen eines Organs und die häufigste Ursache der Hypothyreose dar. Die Hashimotothyreoiditis (HT) weist eine hohe Prävalenz und Inzidenz auf. Es existieren Hinweise, dass die Inzidenz der HT aus noch nicht geklärten Gründen gestiegen sein könnte.
Die Kohlenhydrate Fruktose, Laktose und Sorbitol werden in der Lebensmittelproduktion umfassend eingesetzt. Insbesondere die industrielle Verwendung sowie der weltweite Konsum von Fruktose und Laktose unterlagen in den letzten Jahrzehnten einer rasanten Steigerung, obwohl ein hoher Prozentsatz der Bevölkerung zur Malassimilation jener Kohlenhydrate prädisponiert ist.
In einer internistischen Praxis (Praxis Frau Dr. med. I. Heckl, Bad Homburg) zeigte sich, dass HT-Patienten trotz verifizierter Euthyreose vermehrt über gastrointestinale Symptome berichteten. Unter anderem wurden eine bakterielle Fehlbesiedelung des Dünndarmes und eine Zöliakie ausgeschlossen. In der weiteren Abklärung durch die Praxis Dr. I. Heckl wurde eine deutliche Häufung der Malassimilation der Kohlenhydrate Fruktose, Laktose oder Sorbitol unter euthyreoten HT-Patienten ersichtlich. In Abhängigkeit von einer konsequenten Nahrungsumstellung normalisierten sich regelmäßig das Befinden der Patienten sowie die sonographischen, die serologischen und die laborchemischen Marker der HT, sodass man einen ursächlichen Zusammenhang empirisch vermuten konnte.
Im Rahmen einer prospektiven Studie sollte dieser neu beobachtete Zusammenhang zwischen der HT und der Kohlenhydratmalassimilation in der Klinik und Poliklinik für Nuklearmedizin der Universität Würzburg untersucht werden.
In einem unizentrischen Fall-Kontroll-Studiendesign wurden 45 euthyreote HT-Patienten und 38 schilddrüsengesunde Kontrollpersonen auf das Vorliegen einer Kohlenhydratmalassimilation mittels des Wasserstoffatemtests (H2-Atemtest) untersucht. Alle Probanden erhielten einen Fruktose-H2-Atemtest sowie einen Laktose-H2-Atemtest inklusive einer kapillären Blutglukosemessung. Im Falle eines positiven Ergebnisses des Fruktose-H2-Atemtests wurde ein Glukose-H2-Atemtest zum Ausschluss einer bakteriellen Fehlbesiedelung des Dünndarmes durchgeführt. Lieferte der Fruktose-H2-Atemtest ein negatives Ergebnis, so folgte ein H2-Atemtest mit Sorbitol. Das Auftreten gastrointestinaler Symptome während der Testdurchführung wurde dokumentiert. Symptomfragebögen und semiquantitative Ernährungsfragebögen im retrospektiven Design dienten der Erfassung alltäglicher Symptome und Ernährungsgewohnheiten. Blutproben dienten der Messung von Schilddrüsenhormonen, Schilddrüsenautoantikörpern, Gewebstransglutaminase-Antikörpern und Antiparietalzell-Autoantikörpern.
Unter den euthyreoten HT-Patienten konnte ein signifikant häufigeres Auftreten der Fruktose- sowie der Laktosemalassimilation im Vergleich zu den schilddrüsengesunden Kontrollpersonen demonstriert werden. Die Fruktosemalassimilation wurde bei den HT-Patienten mit 48,9% signifikant häufiger als in der Kontrollgruppe nachgewiesen (p=0,035). Im Kontrollgruppenkollektiv hatte eine Fruktosemalassimilation lediglich bei 26,3% der Probanden bestanden. Eine Laktosemalassimilation wurde bei den HT-Patienten mit 42,2% signifikant häufiger als im Kontrollkollektiv diagnostiziert, welches in 21,1% der Fälle eine Laktosemalassimilation aufwies (p=0,04). Insgesamt lag eine Fruktose- und / oder Laktosemalassimilation bei 73,3% der HT-Patienten und bei 42,1% der Kontrollgruppenprobanden vor. Somit vertrugen nur 26,7% der Fallgruppe, jedoch 57,9% der Kontrollgruppe beide Kohlenhydrate (p=0,004). Hinsichtlich der Prävalenz der Sorbitolmalassimilation oder eines positiven Glukose-H2-Atemtestes kam kein signifikanter Unterschied zur Darstellung. Die Auswertung der Ernährungsfragebögen zeigte für beide Kollektive eine vergleichbare durchschnittliche Konsummenge der jeweiligen Kohlenhydrate auf.
Gastrointestinale Symptome waren während des Laktose-H2-Atemtests sowie während des Fruktose-H2-Atemtests jeweils in der Fallgruppe signifikant häufiger anzutreffen als in der Kontrollgruppe. Auch im Hinblick auf das Alltagsleben beschrieben die euthyreoten HT-Patienten signifikant häufiger unter den folgenden Symptomen zu leiden: Weicher Stuhlgang, Oberbauchschmerzen, Meteorismus, laute Darmgeräusche, „Kugelbauch“, Sodbrennen, Schleimauflagerungen des Stuhlgangs, Obstipation, Müdigkeit, postprandiale Kraftlosigkeit, Depressionen, Heißhunger auf Süßes, Migräne, Konzentrationsmangel und eine vermehrte Infektanfälligkeit.
Zur Kausalität des hier erstmals beschriebenen Zusammenhangs existieren mehrere Hypothesen. Die Einteilung der HT-Patienten gemäß ihrer Schilddrüsenautoantikörper-Titer in Subkollektive ergab keinen Hinweis auf einen Einfluss der Aktivität des Autoimmungeschehens auf die Häufigkeit der Kohlenhydratmalassimilation. Es steht zur Diskussion, ob die HT zur Entstehung einer Kohlenhydratmalassimilation führen, oder ob eine vorbestehende Kohlenhydratmalassimilation, im Sinne eines neu identifizierten Risikofaktors, zur Genese einer HT prädisponieren könnte.
In der vorliegenden Studie konnte erstmalig eine signifikante Häufung der Kohlenhydratmalassimilation bei euthyreoten HT-Patienten aufgezeigt werden. Vor dem Hintergrund der weitreichenden lebensmittelindustriellen Verwendung und des hohen Konsums der Kohlenhydrate Fruktose, Laktose und Sorbitol sowie der hohen Prävalenz und Inzidenz der HT, ergibt sich eine hohe Relevanz des hier nachgewiesenen Zusammenhangs. In der differenzialdiagnostischen Abklärung gastrointestinaler Beschwerden bei euthyreoten HT-Patienten nimmt die hier beschriebene Assoziation zwischen der HT und der Kohlenhydratmalassimilation einen besonderen Stellenwert ein. Die Kohlenhydratmalassimilation verkörpert einen neuen, sowohl klinisch, als auch potentiell pathogenetisch relevanten Aspekt der Hashimotothyreoiditis.
Die Detektion des Prostataspezifischen Membranantigens (PSMA) mittels kombinierter Positronenemissions- und Computertomographie (PET/CT) ist ein etabliertes diagnostisches Verfahren bei Patienten mit Prostatakarzinom. Hierbei ist bislang unklar, ob und wie eine bereits eingeleitete Androgendeprivationstherapie (ADT) die diagnostische Genauigkeit der PSMA-PET/CT beeinflusst. Ziel dieser Arbeit war es, die Detektionsrate der PSMA-PET/CT mit 68Ga-PSMA I&T unter ADT in Abhängigkeit des PSA-Wertes zu evaluieren und mit einer Kontrollgruppe ohne ADT zu vergleichen. In dieser retrospektiven Studie wurden Daten von Patienten mit biochemischem Rezidiv nach radikaler Prostatektomie analysiert, welche zwischen 2014 und 2018 eine PSMA-PET/CT am Universitätsklinikum Würzburg erhalten haben. Mittels Propensity Score Matching wurde für die Patienten mit ADT innerhalb der letzten 6 Monate vor Durchführung der PSMA-PET/CT eine Kontrollgruppe ohne ADT erstellt. Die Patienten mit ADT (n=62) wiesen eine signifikant höhere Detektionsrate auf als die Patienten ohne ADT (n=62). Die Traceranreicherung unterschied sich nicht signifikant in beiden Gruppen. Dagegen wiesen die Patienten mit ADT jedoch eine signifikant höhere Tumorlast auf und hatten häufiger Knochen- und Organmetastasen, sodass als Ursache für die höhere Detektionsrate der PSMA-PET/CT bei Patienten mit ADT ein fortgeschritteneres Tumorstadium angenommen wurde. Die Detektionsrate war bei den Patienten mit ADT auch bei niedrigen PSA-Werten hoch. Es scheint daher nicht erforderlich zu sein, eine bestehende ADT vor Durchführung der PSMA-PET/CT im biochemischen Rezidiv abzusetzen und damit das Risiko einer Krankheitsprogression einzugehen. Die Korrelation des PSA-Wertes mit der Tumorlast in der PSMA-PET/CT war bei Patienten mit ADT geringer ausgeprägt als bei Patienten ohne ADT. Patienten unter ADT könnten daher von einer regelmäßigen Durchführung der PSMA-PET/CT zur Überwachung der Krankheitsprogression profitieren. Hier bleibt allerdings eine Kosten-Nutzen-Analyse abzuwarten, da dies deutlich aufwendiger und teurer ist als die Bestimmung des PSA-Wertes.
Die molekularen Parameter PSMA-TV und TL-PSMA im 68Ga-PSMA PET/CT leiten sich ab von MTV und TLG im FDG PET/CT. Mit der vorliegenden Arbeit wurden die Grenzen neuer Autosegmentierungsprogramme durch eine maximale Belastung mit großen Tumorvolumina von Patienten unter taxanbasierter Chemotherapie ausgelotet. Die Programme Syngo.via und FIJI kamen zu vergleichbaren Ergebnissen. Patienten mit einem Gleason Score von 8-10 zeigten unter Therapie eine signifikante Zunahme des PSMA-TV und TL-PSMA im Gegensatz zu Patienten mit Gleason Score 6-7b. Ein hoher PSA-Wert korrelierte zu allen Zeitpunkten signifikant mit einem hohen PSMA-TV und TL-PSMA, ebenso korrelierte ein steigender PSA-Wert signifikant mit steigenden Werten in PSMA-TV und TL-PSMA. Patienten mit einem biochemischen Progress und einem Progress nach modifiziertem PERCIST zeigten vor Therapie ein signifikant höheres PSMA-TV und TL-PSMA als Patienten ohne Progress und unter Therapie eine signifikante Zunahme des PSMA-TV und TL-PSMA im Vergleich zu Patienten ohne Progress. Eine Einteilung des Therapieansprechens aller Patienten in CR, PR, SD und PD nach PSMA-TV, TL-PSMA, PSA-Wert und modifiziertem PERCIST stimmte nicht in allen Patienten überein. Ein signifikant kürzeres Gesamtüberleben zeigten lediglich Patienten mit einem nach dem PSA-Wert definiertem Progress. Im praktischen Vergleich der beiden Programme benötigte Syngo.via für eine komplette Segmentierung signifikant mehr Zeit als FIJI, vor allem da der Wechsel von VOI zu VOI signifikant länger dauerte. Unabhängig vom Autosegmentierungsprogramm dauerte eine komplette Segmentierung länger, je größer das PSMA-TV und das TL-PSMA war, je mehr VOIs das Programm automatisch setzte und je mehr VOIs manuell gelöscht und neu gesetzt wurden. In der Gesamtschau bieten PSMA-TV und TL-PSMA in Kombination mit den sich schnell weiterentwickelnden Autosegmentierungs-Programmen die Möglichkeit, auch sehr hohe Tumorlasten des PCas objektiv und vergleichbar zu beschreiben.
Purpose
Adrenal tumors represent a diagnostic and therapeutic challenge. Promising results have been obtained through targeting the cytochrome P450 enzymes CYP11B1 and CYP11B2 for molecular imaging, and [\(^{123/131}\)I]iodometomidate ([\(^{123/131}\)I]IMTO) has even been successfully introduced as a theranostic agent. As this radiopharmaceutical shows rapid metabolic inactivation, we aimed at developing new improved tracers.
Methods
Several IMTO derivatives were newly designed by replacing the unstable methyl ester by different carboxylic esters or amides. The inhibition of aldosterone and cortisol synthesis was tested in different adrenocortical cell lines. The corresponding radiolabeled compounds were assessed regarding their stability, in vitro cell uptake, in vivo biodistribution in mice, and their binding specificity to cryosections of human adrenocortical and non-adrenocortical tissue. Furthermore, a first investigation was performed in patients with known metastatic adrenal cancer using both [\(^{123}\)I]IMTO and the most promising compound (R)-1-[1-(4-[\(^{123/}\)I]iodophenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinylamide ([\(^{123}\)I]IMAZA) for scintigraphy. Subsequently, a first endoradiotherapy with [\(^{131}\)I]IMAZA in one of these patients was performed.
Results
We identified three analogues to IMTO with high-affinity binding to the target enzymes and comparable or higher metabolic stability and very high and specific accumulation in adrenocortical cells in vitro and in vivo. Labeled IMAZA exhibited superior pharmacokinetic and imaging properties compared to IMTO in mice and 3 patients, too. An endoradiotherapy with [\(^{131}\)I]IMAZA induced a 21-month progression-free interval in a patient with rapidly progressing ACC prior this therapy.
Conclusion
We developed the new radiopharmaceutical [\(^{123/131}\)I]IMAZA with superior properties compared to the reference compound IMTO and promising first experiences in humans.
Purpose
Repeat surgery in patients with primary hyperparathyroidism (pHPT) is associated with an increased risk of complications and failure. This stresses the need for optimized strategies to accurately localize a parathyroid adenoma before repeat surgery is performed. However, evidence on the extent of required diagnostics for a structured approach is sparse.
Methods
A retrospective single-center evaluation of 28 patients with an indication for surgery due to pHPT and previous thyroid or parathyroid surgery was performed. Diagnostic workup, surgical approach, and outcome in terms of complications and successful removement of parathyroid adenoma with biochemical cure were evaluated.
Results
Neck ultrasound, sestamibi scintigraphy, C11-methionine PET-CT, and selective parathyroid hormone venous sampling, but not MRI imaging, effectively detected the presence of a parathyroid adenoma with high positive predictive values. Biochemical cure was revealed by normalization of calcium and parathormone levels 24-48h after surgery and was achieved in 26/28 patients (92.9%) with an overall low rate of complications. Concordant localization by at least two diagnostic modalities enabled focused surgery with success rates of 100%, whereas inconclusive localization significantly increased the rate of bilateral explorations and significantly reduced the rate of biochemical cure to 80%.
Conclusion
These findings suggest that two concordant diagnostic modalities are sufficient to accurately localize parathyroid adenoma before repeat surgery for pHPT. In cases of poor localization, extended diagnostic procedures are warranted to enhance surgical success rates. We suggest an algorithm for better orientation when repeat surgery is intended in patients with pHPT.
Despite improved survival in the Rituximab (R) era, a considerable number of patients with diffuse large B-cell lymphoma (DLBCL) ultimately die from the disease. Functional imaging using [18F]fluorodeoxyglucose-PET is suggested for assessment of residual viable tumor very early during treatment but is compromised by non-specific tracer retention in inflammatory lesions. The PET tracer [18F]fluorodeoxythymidine (FLT) as surrogate marker of tumor proliferation may overcome this limitation. We present results of a prospective clinical study testing FLT-PET as superior and early predictor of response to chemotherapy and outcome in DLBCL. 54 patients underwent FLT-PET prior to and one week after the start of R-CHOP chemotherapy. Repetitive FLT-PET imaging was readily implemented into the diagnostic work-up. Our data demonstrate that the reduction of FLT standard uptake valuemean (SUVmean) and SUVmax one week after chemotherapy was significantly higher in patients achieving complete response (CR, n=48; non-CR, n=6; p<0.006). Martingale-residual and Cox proportional hazard analyses showed a significant monotonous decrease of mortality risk with increasing change in SUV. Consistent with these results, early FLT-PET response showed relevant discriminative ability in predicting CR. In conclusion, very early FLT-PET in the course of R-CHOP chemotherapy is feasible and enables identification of patients at risk for treatment failure.
Background: Use of FDG-PET/CT for staging and restaging of lymphoma patients is widely incorporated into current practice guidelines. Our aim was to prospectively evaluate the diagnostic performance of FDG-PET/MRI and WB-DW-MRI compared with FDG-FDG-PET/CT using a tri-modality PET/CT-MRI system.
Methods: From 04/12 to 01/14, a total of 82 FDG-PET/CT examinations including an additional scientific MRI on a tri-modality setup were performed in 61 patients. FDG-PET/CT, FDG-PET/MRI, and WB-DW-MRI were independently analyzed. A lesion with a mean ADC below a threshold of 1.2 x 10\(^{-3}\) mm\(^2\)/s was defined as positive for restricted diffusion. FDG-PET/CT and FDG-PET/MRI were evaluated for the detection of lesions corresponding to lymphoma manifestations according to the German Hodgkin Study Group. Imaging findings were validated by biopsy (n = 21), by follow-up imaging comprising CT, FDG-PET/CT, and/or FDG-PET/MRI (n = 32), or clinically (n = 25) (mean follow-up: 9.1 months).
Results: FDG-PET/MRI and FDG-PET/CT accurately detected 188 lesions in 27 patients. Another 54 examinations in 35 patients were negative. WB-DW-MRI detected 524 lesions, of which 125 (66.5 % of the aforementioned 188 lesions) were true positive. Among the 188 lesions positive for lymphoma, FDG-PET/MRI detected all 170 instances of nodal disease and also all 18 extranodal lymphoma manifestations; by comparison, WB-DW-MRI characterized 115 (67.6 %) and 10 (55.6 %) lesions as positive for nodal and extranodal disease, respectively. FDG-PET/MRI was superior to WB-DW-MRI in detecting lymphoma manifestations in patients included for staging (113 vs. 73), for restaging (75 vs. 52), for evaluation of high-(127 vs. 81) and low-grade lymphomas (61 vs. 46), and for definition of Ann Arbor stage (WB-DW-MRI resulted in upstaging in 60 cases, including 45 patients free of disease, and downstaging in 4).
Conclusion: Our results indicate that FDG-PET/CT and FDG-PET/MRI probably have a similar performance in the clinical work-up of lymphomas. The performance of WB-DW-MRI was generally inferior to that of both FDG-PET-based methods but the technique might be used in specific scenarios, e.g., in low-grade lymphomas and during surveillance.
Various single or multi-modality therapeutic options are available to treat pain of bone metastasis in patients with prostate cancer. Different radionuclides that emit β-rays such as 153Samarium and 89Strontium and achieve palliation are commercially available. In contrast to β-emitters, 223Radium as a α-emitter has a short path-length. The advantage of the α-emitter is thus a highly localized biological effect that is caused by radiation induced DNA double-strand breaks and subsequent cell killing and/or limited effectiveness of cellular repair mechanisms. Due to the limited range of the α-particles the bone surface to red bone marrow dose ratio is also lower for 223Radium which is expressed in a lower myelotoxicity. The α emitter 223Radium dichloride is the first radiopharmaceutical that significantly prolongs life in castrate resistant prostate cancer patients with wide-spread bone metastatic disease. In a phase III, randomized, double-blind, placebo-controlled study 921 patients with castration-resistant prostate cancer and bone metastases were randomly assigned. The analysis confirmed the 223Radium survival benefit compared to the placebo (median, 14.9 mo vs 11.3 mo; P < 0.001). In addition, the treatment results in pain palliation and thus, improved quality of life and a delay of skeletal related events. At the same time the toxicity profile of 223Radium was favourable. Since May 2013, 223Radium dichloride (Xofigo®) is approved by the US Food and Drug Administration.
Core tip: The incidence rate of prostate cancer worldwide is high. Ninety percent of patients dying of prostate cancer have bone metastases with varying symptoms which are significantly impairing their quality of life. 223Radium is the first therapeutic that results in a survival benefit for patients with bone metastatic, castrate resistant prostate cancer. 223Radium was also associated with low myelosuppression rates and fewer adverse events.This article provides an overview of the pre-clinical and clinical trials with 223Radium.
Purpose of Review
Statins are routinely applied in patients with coronary artery disease, as they allow significantly to reduce blood cholesterol levels. Although those drugs are endorsed by current guidelines and prescribed routinely, a substantial portion of patients are still statin-intolerant and image-piloted strategies may then be helpful to identify patients that need further intensified treatment, e.g., to initiate treatment with proprotein convertase subtilisin / kexin type 9 inhibitors (PCSK9i). In addition, it has also been advocated that statins exhibit nonlipid, cardio-protective effects including improved cardiac nerve integrity, blood flow, and anti-inflammatory effects in congestive heart failure (HF) patients.
Recent Findings
In subjects after myocardial infarction treated with statins, \(^{123}\)I-metaiodobenzylguanidine (MIBG) scintigraphy has already revealed enhanced cardiac nerve function relative to patients without statins. In addition, all of those aforementioned statin-targeted pathways in HF can be visualized and monitored using dedicated cardiac radiotracers, e.g., \(^{123}\)I-MIBG or \(^{18}\)F-AF78 (for cardiac nerve function), \(^{18}\)F-flurpiridaz (to determine coronary flow) or \(^{68}\)Ga-PentixaFor (to detect inflammation).
Summary
Statins exhibit various cardio-beneficial effects, including improvement of cardiac nerve function, blood flow, and reduction of inflammation, which can all be imaged using dedicated nuclear cardiac radiotracers. This may allow for in vivo monitoring of statin-induced cardioprotection beyond lipid profiling in HF patients.
Ziel der Studie lag in der Analyse des Zusammenhangs von Muskel- und Knochenmasse als Surrogat für Kraft und Knochenfestigkeit. In der vorliegenden Arbeit wurden 265 gesunde und chronisch kranke Kinder und Jugendliche auf ihre Körperzusammensetzung untersucht.(Anorexia nervosa: 40, Hypophosphatasie: 10, Kraniopharyngeom: 12 und juveniles Rheuma: 68, Referenzgruppe: 79 gesunde weissrussische Mädchen und 56 Jungen). Die Untersuchungsergebnisse der DXA Messungen bestätigen , dass die Knochenmasse als Surrogat für Festigkeit eng mit der Muskelmasse korreliert. Mit zunehmender Muskelmasse steigt auch der BMC an. Die Ergebnisse der Studie stehen im Einklang mit dem von Frost postuliertem Regelkreis, der einen kausalen Zusammenhang zwischen Muskelkraft und Knochenfestigkeit beschrieb. Generell zeigte sich, dass das Surrogat Knochendichte diesen Zusammenhang weniger scharf beschreibt als die Knochenmasse. Darüber hinaus fanden sich Störungen des Regelkreises, deren Ursachen zum Teil Gegenstand der Abklärung in weiterführenden Studien bleiben.
Background
Small-animal single-photon emission computed tomography (SPECT) systems with multi-pinhole collimation and large stationary detectors have advantages compared to systems with moving small detectors. These systems benefit from less labour-intensive maintenance and quality control as fewer prone parts are moving, higher accuracy for focused scans and maintaining high resolution with increased sensitivity due to focused pinholes on the field of view. This study aims to investigate the performance of a novel ultra-high-resolution scanner with two-detector configuration (U-SPECT5-E) and to compare its image quality to a conventional micro-SPECT system with three stationary detectors (U-SPECT\(^+\)).
Methods
The new U-SPECT5-E with two stationary detectors was used for acquiring data with \(^{99m}\)Tc-filled point source, hot-rod and uniformity phantoms to analyse sensitivity, spatial resolution, uniformity and contrast-to-noise ratio (CNR). Three dedicated multi-pinhole mouse collimators with 75 pinholes each and 0.25-, 0.60- and 1.00-mm pinholes for extra ultra-high resolution (XUHR-M), general-purpose (GP-M) and ultra-high sensitivity (UHS-M) imaging were examined. For CNR analysis, four different activity ranges representing low- and high-count settings were investigated for all three collimators. The experiments for the performance assessment were repeated with the same GP-M collimator in the three-detector U-SPECT\(^+\) for comparison.
Results
Peak sensitivity was 237 cps/MBq (XUHR-M), 847 cps/MBq (GP-M), 2054 cps/MBq (UHS-M) for U-SPECT5-E and 1710 cps/MBq (GP-M) for U-SPECT\(^+\). In the visually analysed sections of the reconstructed mini Derenzo phantoms, rods as small as 0.35 mm (XUHR-M), 0.50 mm (GP-M) for the two-detector as well as the three-detector SPECT and 0.75 mm (UHS-M) were resolved. Uniformity for maximum resolution recorded 40.7% (XUHR-M), 29.1% (GP-M, U-SPECT5-E), 16.3% (GP-M, U-SPECT\(^+\)) and 23.0% (UHS-M), respectively. UHS-M reached highest CNR values for low-count images; for rods smaller than 0.45 mm, acceptable CNR was only achieved by XUHR-M. GP-M was superior for imaging rods sized from 0.60 to 1.50 mm for intermediate activity concentrations. U-SPECT5-E and U-SPECT+ both provided comparable CNR.
Conclusions
While uniformity and sensitivity are negatively affected by the absence of a third detector, the investigated U-SPECT5-E system with two stationary detectors delivers excellent spatial resolution and CNR comparable to the performance of an established three-detector-setup.
SPECT as a representative of molecular imaging allows visualization of metabolic processes in vivo. In clinical practice, single photon emission imaging is an established modality for myocardial perfusion imaging or the diagnosis of adrenal or neuroendocrine tumors, to name a few. With technical advances in scanner design and data processing leading to improved spatial resolution and image quality, SPECT has become a serious contender in small animal preclinical imaging. With multi-pinhole collimation, submillimeter spatial resolutions are achieved without limiting sensitivity, which has led to a significant increase of interest in SPECT for preclinical research in recent years.
In this dissertation, the potential of a two-detector system through an analysis of three dedicated mouse collimators with multi-pinhole configurations was demonstrated. For this, sensitivity, spatial resolution, and uniformity as key parameters were determined. In the second part of the present work, an evaluation of the image quality at different activity concentrations to allow prediction of the system performance related to in vivo studies was performed. Therefore, a visual evaluation, as well as a calculation of the contrastto-noise ratio, was performed using mini Derenzo phantoms for the respective three mouse collimators. To better classify the results, the study was extended by a comparison with the predecessor system.
Due to the absence of the third bottom detector, sensitivity and uniformity are slightly compromised. All three collimators were able to achieve a spatial resolution in the submillimeter range, XUHR-M offers a peak resolution of up to 0.35 mm. In terms of resolution, both evaluated systems performed on an equal level. Visual assessment of image quality indicates a slight advantage of the new two-detector system, and the contrast-to-noise ratio seems to benefit from the improved SROSEM algorithm. However, the differences between the two systems are marginal.
The U-SPECT5/CT E-Class is proven to be state-of-the-art for small animal imaging and is a powerful instrument for preclinical molecular imaging research. Improvements in system design compensate well for the reduction in the detection area, allowing excellent imaging even with low activity concentrations.
Purpose
The radiolabelled somatostatin analogue [\(^{177}\)Lu]Lu-DOTA-EB-TATE binds to albumin via Evans blue, thereby increasing the residence time in the blood and potentially allowing more therapeutic agent to be absorbed into the target tissue during peptide receptor radionuclide therapy. It was tested in selected patients whether the substance is superior to [\(^{177}\)Lu]Lu-DOTA-TOC.
Methods
Activity kinetics in organs and tumours after [\(^{177}\)Lu]Lu-DOTA-EB-TATE and [\(^{177}\)Lu]Lu-DOTA-TOC were compared intraindividually in five patients with progressive somatostatin receptor-positive disease scheduled for radionuclide therapy.
Resuluts
In comparison to [\(^{177}\)Lu]Lu-DOTA-TOC, tumour doses per administered activity were higher for [\(^{177}\)Lu]Lu-DOTA-EB-TATE in 4 of 5 patients (median ratio: 1.7; range: 0.9 to 3.9), kidney doses (median ratio: 3.2; range: 1.6 to 9.8) as well as spleen doses (median ratio: 4.7; range 1.2 to 6.2) in all patients, and liver doses in 3 of 4 evaluable patients (median ratio: 4.0; range: 0.7 to 4.9). The tumour to critical organs absorbed dose ratios were higher after [\(^{177}\)Lu]Lu-DOTA-TOC in 4 of 5 patients.
Conclusions
Prior to a treatment with [\(^{177}\)Lu]Lu-DOTA-EB-TATE, it should be assessed individually whether the compound is superior to established substances.
Der spezifischste und sensitivste biochemische Tumormarker in der Diagnostik und Verlaufskontrolle des MTC ist Kalzitonin. Der hCT-Spiegel sollte nach totaler Thyreoidektomie nicht mehr messbar sein. Ein messbares hCT weist nach Therapie auf ein Rezidiv oder eine Metastasierung hin. Die hCT-Sekretion kann durch Gastrin stimuliert werden, was beim Pentagastrin-Stimulationstest genutzt wird. Im Rahmen dieser Arbeit wurde untersucht, welchen Stellenwert die Bestimmung des basalen Kalzitonin im Vergleich zum Pentagastrin-stimulierten hCT in der Nachsorge des MTC einnimmt. Hierzu wurden 129 Pentagastrintests von MTC-Patienten der Klinik und Poliklinik für Nuklearmedizin der Universität Würzburg retrospektiv ausgewertet. Bei sechs Prozent der Patienten fand sich nach anfänglicher biochemischer Remission ein hCT-Anstieg. Die im Pentagastrintest stimulierten hCT-Werte zeigten den Anstieg früher an als die lediglich basal gemessenen Werte. Das Ergebnis dieser Arbeit lässt den Schluss zu, dass der Pentagastrintest weiterhin ein wichtiger Bestandteil in der Nachsorge von Patienten mit MTC ist, da die stimulierten hCT-Werte im Einzelfall eine noch subklinische residuelle Erkrankung, Metastasierung oder ein Rezidiv frühzeitig detektieren.
Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 % suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a standardized peripheral nerve crush lesion in wild type (wt) and Tor1a+/- mice, that express 50 % torsinA only, was assessed by scoring of hindlimb movements during tail suspension, by rotarod testing and by computer-assisted gait analysis. Western blot analysis was performed for dopamine transporter (DAT), D1 and D2 receptors from striatal and quantitative RT-PCR analysis for DAT from midbrain dissections. Autoradiography was used to assess the functional DAT binding in striatum. Striatal dopamine and its metabolites were analyzed by high performance liquid chromatography. After nerve crush injury, we found abnormal posturing in the lesioned hindlimb of both mutant and wt mice indicating the profound influence of the nerve lesion (15x vs. 12x relative to control) resembling human peripheral pseudodystonia. In mutant mice the phenotypic abnormalities were increased by about 40 % (p < 0.05). This was accompanied by complex alterations of striatal dopamine homeostasis. Pharmacological blockade of dopamine synthesis reduced severity of dystonia-like movements, whereas treatment with L-Dopa aggravated these but only in mutant mice suggesting a DYT1 related central component relevant to the development of abnormal involuntary movements. Our findings suggest that upon peripheral nerve injury reduced torsinA concentration and environmental stressors may act in concert in causing the central motor network dysfunction of DYT1 dystonia.
Pathophysiological understanding of gait and balance disorders in Parkinson’s disease is insufficient and late recognition of fall risk limits efficacious followup to prevent or delay falls. We show a distinctive reduction of glucose metabolism in the left posterior parietal cortex, with increased metabolic activity in the cerebellum, in parkinsonian patients 6–8 months before their first fall episode. Falls in Parkinson’s disease may arise from altered cortical processing of body spatial orientation, possibly predicted by abnormal cortical metabolism.
We investigated in vivo brain nicotinic acetylcholine receptor (nAChR) distribution in cognitively intact subjects with Parkinson's disease (PD) at an early stage of the disease. Fourteen patients and 13 healthy subjects were imaged with single photon emission computed tomography and the radiotracer 5-[(123)I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine ([(123)I]5IA). Patients were selected according to several criteria, including short duration of motor signs (<7 years) and normal scores at an extensive neuropsychological evaluation. In PD patients, nAChR density was significantly higher in the putamen, the insular cortex and the supplementary motor area and lower in the caudate nucleus, the orbitofrontal cortex, and the middle temporal gyrus. Disease duration positively correlated with nAChR density in the putamen ipsilateral (ρ = 0.56, p < 0.05) but not contralateral (ρ = 0.49, p = 0.07) to the clinically most affected hemibody. We observed, for the first time in vivo, higher nAChR density in brain regions of the motor and limbic basal ganglia circuits of subjects with PD. Our findings support the notion of an up-regulated cholinergic activity at the striatal and possibly cortical level in cognitively intact PD patients at an early stage of disease.
Background
Traumatic brain injury (TBI) is a major cause of death and disability. Neuroinflammation contributes to acute damage after TBI and modulates long-term evolution of degenerative and regenerative responses to injury. The aim of the present study was to evaluate the relationship of microglia activation to trauma severity, brain energy metabolism, and cellular reactions to injury in a mouse closed head injury model using combined in vivo PET imaging, ex vivo autoradiography, and immunohistochemistry.
Methods
A weight-drop closed head injury model was used to produce a mixed diffuse and focal TBI or a purely diffuse mild TBI (mTBI) in C57BL6 mice. Lesion severity was determined by evaluating histological damage and functional outcome using a standardized neuroscore (NSS), gliosis, and axonal injury by immunohistochemistry. Repeated intra-individual in vivo μPET imaging with the specific 18-kDa translocator protein (TSPO) radioligand [\(^{18}\)F]DPA-714 was performed on day 1, 7, and 16 and [\(^{18}\)F]FDG-μPET imaging for energy metabolism on days 2–5 after trauma using freshly synthesized radiotracers. Immediately after [\(^{18}\)F]DPA-714-μPET imaging on days 7 and 16, cellular identity of the [\(^{18}\)F]DPA-714 uptake was confirmed by exposing freshly cut cryosections to film autoradiography and successive immunostaining with antibodies against the microglia/macrophage marker IBA-1.
Results
Functional outcome correlated with focal brain lesions, gliosis, and axonal injury. [\(^{18}\)F]DPA-714-μPET showed increased radiotracer uptake in focal brain lesions on days 7 and 16 after TBI and correlated with reduced cerebral [\(^{18}\)F]FDG uptake on days 2–5, with functional outcome and number of IBA-1 positive cells on day 7. In autoradiography, [\(^{18}\)F]DPA-714 uptake co-localized with areas of IBA1-positive staining and correlated strongly with both NSS and the number of IBA1-positive cells, gliosis, and axonal injury. After mTBI, numbers of IBA-1 positive cells with microglial morphology increased in both brain hemispheres; however, uptake of [\(^{18}\)F]DPA-714 was not increased in autoradiography or in μPET imaging.
Conclusions
[\(^{18}\)F]DPA-714 uptake in μPET/autoradiography correlates with trauma severity, brain metabolic deficits, and microglia activation after closed head TBI.