Automated synthesis of [68Ga]Ga-FAPI-46 without pre-purification of the generator eluate on three common synthesis modules and two generator types

Background The recent development of quinoline-based radiotracers, which act as fibroblast activation protein inhibitors (FAPIs), has shown promising preclinical and clinical advantages. [68Ga]Ga-FAPI-46 is a new radiotracer for in vivo detection of the fibroblast activation protein by positron emission tomography (PET). Recently, the automated synthesis of [68Ga]Ga-FAPI-46 was reported based on pre-concentration and purification of the generator eluate by using a cation exchange-cartridge. Our aim was to simplify the synthesis and shorten the automated synthesis of [68Ga]Ga-FAPI-46 to make it accessible and thus even more attractive to a broader clinical and scientific community. Results We developed and evaluated the GMP compliant automatic synthesis of [68Ga]Ga-FAPI-46 using two different 68Ge/68Ga generators (an Eckert & Ziegler, GalliaPharm generator, 1.85 GBq/50 mCi and an iThemba generator, 1.85 GBq/50 mCi) Somerset West, South Africa) and three different commercial and customized systems: the EasyOne module from Trasis; the GaSy module from Synthra with a customized synthesis template and a customized single use cassette. Additionally, the automatic synthesis of [68Ga]Ga-FAPI-46 was established on a GallElut synthesis module from Scintomics with fixed tubing. Conclusions Independent of the synthesis modules or the generators employed we were able to complete the synthesis of [68Ga]Ga-FAPI-46 in 12 min including the process of purification and formulation. In all cases, the final products showed more than 99.5% chemical purity and the radiochemical yield reached around 92.5% (decay corrected). All quality control parameters (e.g. sterility, stability and radiochemical purity) were conform to the European Pharmacopoeia

Pre- and intratherapeutic predictors of overall survival in patients with advanced metastasized castration-resistant prostate cancer receiving Lu-177-PSMA-617 radioligand therapy

Background Systemic Lutetium-177 prostate-specific membrane antigen-617 radioligand therapy (Lu-177-PSMA-617-RLT) is a novel treatment approach in patients suffering from metastasized castration-resistant prostate cancer. Nonetheless, a therapeutic response may fail to appear in a proportion of patients. This study aims to identify routinely obtainable pre- and intratherapeutic parameters to allow a prediction of overall survival in patients receiving Lu-177-PSMA-617 radioligand therapy. Methods Between January 2015 and December 2020 52 patients treated with a total of 146 cycles Lu-177-PSMA-617-RLT were retrospectively analysed in a single-center trial. The median overall survival time (OS) was compared to pre-therapeutic serological parameters, the extend of metastatic spread and previously performed therapies using Kaplan-Meier estimators and multivariate Cox-regression. Bonferroni-Holm correction was performed on all statistical tests. Results The median OS of all patients was 55.6 weeks. Multivariate Cox-regression revealed significant lower survival for decreased pretherapeutic hemoglobin levels (HR 0.698 per g/dl; 95%-CI 0.560-0.872; p = 0.001), increased lactate dehydrogenase (LDH) levels (HR 1.073 per 25 U/l; 95%-CI 1.024-1.125; p = 0.003) and the presence of hepatic metastasis (HR 6.981; 95%-CI 2.583-18.863; p < 0.001). Increased pretherapeutic c-reactive protein (CRP), alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) levels were also associated with a shorter survival. Conclusion Pre-therapeutic hemoglobin and LDH levels, as well as the presence of hepatic metastasis are independent predictors of overall survival in patients receiving Lu-177-PSMA-617-RLT. CRP, ALP and GGT levels cloud be utilized as additional decision aids when a Lu-177-PSMA-617-RLT is intended. Trial Registration Not applicable (retrospective observational study)

New Approach for Analysing the Discrepancy of Pretherapeutic Tc-99m and Intra-therapeutic I-131 uptake in Scintigraphies of Thyroid Autonomies using a Parametric 3D Analysis Programs

<div> <p><small><b>Introduction:</b> Radioiodine therapy is a standard procedure in thyroid autonomy treatment. Discrepancies in the visual comparisons of the scintigraphies prepared for this purpose using Tc-99m-O4- and I-131 have been known for years. In this study a new method is used to calculate and perform a quantitative comparison of both uptakes using subtraction analysis and 3D imaging. The results and their causes are discussed together with practice-relevant conclusions for better clinical results.</small></p> <p><small><b>Material and Methods:</b> The new method was used in 38 patients with thyroid autonomies for the subtraction analysis of standardized pretherapeutic and intratherapeutic scintigraphies. The parametric distribution of activity was calculated absolutely and as a percentage and displayed three-dimensionally. These results were compared with the visual assessment of the different scintigraphies by the experts. Inclusion criteria were pretherapeutic and intratherapeutic hyperthyroidism without medication affecting the thyroid. The time difference between acquiring the scintigraphies was 28 days maximum.</small></p> <p><small><b>Results:</b> Activity distribution was visually discrepant in 39.5% of cases. 60.5% displayed comparable uptake. The calculated values showed reversed results after applying the new method. The results using our method show a higher rate of calculated discrepancies compared with visual analysis.</small></p> <p><small><b>Conclusion:</b> Accurate functional imaging of the thyroid is next to further aspects very important in establishing the diagnosis and deciding about the therapy activity for thyroid treatment. In combination with clinical symptoms and laboratory values, Tc-99m-O4 - scintigram can be used for an orientated, preliminary assessment of functional disorders of the thyroid. But because of the higher rate of found discrepancies, the solely use of Tc-99m-O4 - scintigram is not always capable for exact and reliable diagnosis. The known reason for this is most probably due to the different biokinetics of both radiopharmaceuticals, which can be imaged more sensitively with this method. Consequently, a scintigram should be performed in the pretherapeutic radioiodine uptake test. Despite higher costs and radiation exposure, alternatively, pretherapeutic use of other diagnostic iodine isotopes like I-123 or -124 should be discussed, because they could overcome the limitation of the different biokinetics. Following this approach the preliminary assessment using Tc-99m-O4 - scintigraphy can be precised and double checked to improve diagnostic confi dence and treatment results for a better outcome of the patients.</small></p> </div

New Approach for Analysing the Discrepancy of Pretherapeutic Tc-99m and Intra-therapeutic I-131 uptake in Scintigraphies of Thyroid Autonomies using a Parametric 3D Analysis Program

Introduction: Radioiodine therapy is a standard procedure in thyroid autonomy treatment. Discrepancies in the visual comparisons of the scintigraphies prepared for this purpose using Tc-99m-O4- and I-131 have been known for years. In this study a new method is used to calculate and perform a quantitative comparison of both uptakes using subtraction analysis and 3D imaging. The results and their causes are discussed together with practice-relevant conclusions for better clinical results. Material and Methods: The new method was used in 38 patients with thyroid autonomies for the subtraction analysis of standardized pretherapeutic and intratherapeutic scintigraphies. The parametric distribution of activity was calculated absolutely and as a percentage and displayed three-dimensionally. These results were compared with the visual assessment of the different scintigraphies by the experts. Inclusion criteria were pretherapeutic and intratherapeutic hyperthyroidism without medication affecting the thyroid. The time difference between acquiring the scintigraphies was 28 days maximum. Results: Activity distribution was visually discrepant in 39.5% of cases. 60.5% displayed comparable uptake. The calculated values showed reversed results after applying the new method. The results using our method show a higher rate of calculated discrepancies compared with visual analysis. Conclusion: Accurate functional imaging of the thyroid is next to further aspects very important in establishing the diagnosis and deciding about the therapy activity for thyroid treatment. In combination with clinical symptoms and laboratory values, Tc-99m-O4 - scintigram can be used for an orientated, preliminary assessment of functional disorders of the thyroid. But because of the higher rate of found discrepancies, the solely use of Tc-99m-O4 - scintigram is not always capable for exact and reliable diagnosis. The known reason for this is most probably due to the different biokinetics of both radiopharmaceuticals, which can be imaged more sensitively with this method. Consequently, a scintigram should be performed in the pretherapeutic radioiodine uptake test. Despite higher costs and radiation exposure, alternatively, pretherapeutic use of other diagnostic iodine isotopes like I-123 or -124 should be discussed, because they could overcome the limitation of the different biokinetics. Following this approach the preliminary assessment using Tc-99m-O4 - scintigraphy can be precised and double checked to improve diagnostic confi dence and treatment results for a better outcome of the patients. &nbsp

Case Report: Arterial Wall Inflammation in Atherosclerotic Cardiovascular Disease is Reduced by Olamkicept (sgp130Fc)

Inflammation is a strong driver of atherosclerotic cardiovascular disease (ASCVD). There is a large unmet need for therapies that prevent or reduce excessive inflammation while avoiding systemic immunosuppression. We showed previously that selective inhibition of pro-inflammatory interleukin-6 (IL-6) trans-signalling by the fusion protein olamkicept (sgp130Fc) prevented and reduced experimental murine atherosclerosis in low-density lipoprotein receptor-deficient (Ldlr -/-) mice on a high-fat, high-cholesterol diet independently of low-density lipoprotein (LDL) cholesterol metabolism. Therefore, we allowed compassionate use of olamkicept (600 mg intravenously biweekly for 10 weeks) in a patient with very-high-risk ASCVD. Despite optimal LDL cholesterol under maximum tolerated lipid-lowering treatment, the patient had a remaining very high risk for future cardiovascular events related to significant arterial wall inflammation with lipoprotein (a) [Lp(a)]-cholesterol as the main contributor. 18Fluorodeoxyglucose positron emission tomography/computed tomography (18FDG PET/CT) measurements were performed before and after the treatment period. Olamkicept reduced arterial wall inflammation in this patient without interfering with lipoprotein metabolism. No clinical or laboratory side effects were observed during or after treatment with olamkicept. Our findings in this patient matched the results from our mechanistic study in Ldlr -/- mice, which were extended by additional analyses on vascular inflammation. Olamkicept may be a promising option for treating ASCVD independently of LDL cholesterol metabolism. A Phase II trial of olamkicept in ASCVD is currently being prepared

German Multicenter Study Investigating Lu-177-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer Patients

Lu-177-labeled PSMA-617 is a promising new therapeutic agent for radioligand therapy (RLT) of patients with metastatic castration resistant prostate cancer (mCRPC). Initiated by the German Society of Nuclear Medicine, a retrospective multicenter data analysis was started in 2015 to evaluate efficacy and safety of Lu-177-PSMA-617 in a large cohort of patients. Methods: One hundred forty-five patients (median age, 73 y; range, 43-88 y) with mCRPC were treated with Lu-177-PSMA-617 in 12 therapy centers between February 2014 and July 2015 with 1-4 therapy cycles and an activity range of 2-8 GBq per cycle. Toxicity was categorized by the common toxicity criteria for adverse events (version 4.0) on the basis of serial blood tests and the attending physician's report. The primary endpoint for efficacy was biochemical response as defined by a prostate-specific antigen decline 50% from baseline to at least 2 wk after the start of RLT. Results: A total of 248 therapy cycles were performed in 145 patients. Data for biochemical response in 99 patients as well as data for physician-reported and laboratory-based toxicity in 145 and 121 patients, respectively, were available. The median follow-up was 16 wk (range, 2-30 wk). Nineteen patients died during the observation period. Grade 3-4 hematotoxicity occurred in 18 patients: 10%, 4%, and 3% of the patients experienced anemia, thrombocytopenia, and leukopenia, respectively. Xerostomia occurred in 8%. The overall biochemical response rate was 45% after all therapy cycles, whereas 40% of patients already responded after a single cycle. Elevated alkaline phosphatase and the presence of visceral metastases were negative predictors and the total number of therapy cycles positive predictors of biochemical response. Conclusion: The present retrospective multicenter study of Lu-177-PSMA-617 RLT demonstrates favorable safety and high efficacy exceeding those of other third-line systemic therapies in mCRPC patients. Future phase II/III studies are warranted to elucidate the survival benefit of this new therapy in patients with mCRPC