Support for the "Vancouver call for action to strengthen expertise in radiological protection worldwide": the position of organisations in formal relations with the International Commission on Radiological Protection (ICRP).

The International Commission on Radiological Protection (ICRP), recently expressed concern that "a shortage of investment in training, education, research, and infrastructure seen in many sectors and countries may compromise society's ability to properly manage radiation risks" and in 2022 announced the "Vancouver call for action to strengthen expertise in radiological protection worldwide". As representatives of organisations in formal relations with ICRP, we decided to promote this position paper to declare and emphasise that strengthening the expertise in radiological protection is a collective priority for all of us.

Cerebral glucose metabolic correlates of cognitive and behavioural impairments in amyotrophic lateral sclerosis.

OBJECTIVE: Half of ALS patients are cognitively and/or behaviourally impaired. As cognition/behaviour and cerebral glucose metabolism can be correlated by means of 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET), we aimed to utilise FDG-PET, first, to replicate group-level differences in glucose metabolism between non-demented ALS patients separated into non-impaired (ALSni), cognitively impaired (ALSci), behaviourally impaired (ALSbi), and cognitively and behaviourally impaired (ALScbi) groups; second, to investigate glucose metabolism and performance in various cognitive domains; and third, to examine the impact of partial volume effects correction (PVEC) of the FDG-PET data on the results. METHODS: We analysed neuropsychological, clinical, and imaging data from 67 ALS patients (30 ALSni, 21 ALSci, 5 ALSbi, and 11 ALScbi). Cognition was assessed with the Edinburgh Cognitive and Behavioural ALS Screen, and two social cognition tests. FDG-PET and structural MRI scans were acquired for each patient. Voxel-based statistical analyses were undertaken on grey matter volume (GMV) and non-corrected vs. PVE-corrected FDG-PET scans. RESULTS: ALSci and ALScbi had lower cognitive scores than ALSni. In contrast to both ALSni and ALSci, ALScbi showed widespread hypometabolism in the superior- and middle-frontal gyri in addition to the right temporal pole. Correlations were observed between the GMV, the FDG-PET signal, and various cognitive scores. The FDG-PET results were largely unaffected by PVEC. INTERPRETATION: Our study identified widespread differences in hypometabolism in the ALScbi-ni but not in the ALSci-ni group comparison, raising the possibility that cerebral metabolism may be more closely related to the presence of behavioural changes than to mild cognitive deficits.

Patient-Orientated Evaluation of Treatment of Non-Melanoma Skin Cancer with Rhenium-188 Compared to Surgery.

BACKGROUND: Non-melanoma skin cancers (NMSCs) are responsible for up to one-third of all human malignancies. Surgery is usually the treatment of choice, but patients often experience pain during the procedure. Topical rhenium-188 resin skin cancer treatment (RSCT) may be a valid therapeutic alternative. METHODS: In this monocentric pilot study, 19 patients suffering from NMSC were treated with RSCT. Most of these patients had also experienced surgery, either because they developed a new NMSC in aftercare, or they had suffered previously from NMSC. Three RSCT-treated patients, who had no exposure to surgery so far, were paired with three matched patients, who had received surgery. We sought to evaluate and compare the patients' experience with both treatments. A questionnaire assessed patients' perceptions regarding side effects, aesthetic outcomes, wound care, fear of complications, and personal treatment preferences. Patients evaluated the different parameters of their either RSCT- or surgery-treated lesions on a scale from 0-10. RESULTS: Patients were more afraid of complications before surgery than before RSCT (p = 0.04). Treatment with RSCT caused significantly less pain on treatment day (mean 0.56) than surgery (mean 2.32) (0 no pain, 10 maximum pain) (p = 0.02) and 14 days after the procedure (mean 0.89 versus mean 2.47) (p = 0.02). On day 14, RSCT-treated lesions were also significantly less itchy (mean 0.34) than after surgery (mean 1.50). Most patients were very satisfied with the aesthetic outcome after both RSCT (mean 8.42) and surgery (mean 8.31) (p = 0.89). In the case of a new NMSC, the majority of patients who experienced both treatments would rather be treated primarily with RSCT (44%) or would consider both options (31%); only 19% preferred surgery. CONCLUSION: Patients evaluated RSCT as less painful than surgery. The aesthetic outcomes of both treatments were comparable. For pain-sensitive patients, RSCT might be a preferable treatment option.

Impact of 68Ga-PSMA PET/CT on radiation treatment planning of prostate cancer patients.

AIM: This study aimed to assess the impact of 68Ga-PSMA PET/CT on radiation treatment (RT) planning in prostate cancer patients with salvage (sRT) or definitive (dRT) radiotherapy. METHODS: 38 patients (27 sRT, median PSA 0.79 ng/ml (range 0.06-12.1); 11 dRT, median PSA 4.35 ng/ml (range 1.55-55.5) underwent 68Ga-PSMA PET/CT before RT. Influence of 68Ga-PSMA PET/CT on the extent of planning target volume (PTV) and addition of PET-based boosts were assessed. Median follow up was 12 months (range 3-24). RESULTS: 68Ga-PSMA PET/CT showed positive findings in 23/38 patients (8/23: local recurrence (LR), 11/23: nodal metastasis, 1/23: LR and nodal, 2/23: solitary bone metastasis, 1/23: oligometastatic nodal/ bone metastases). In sRT primary PTV was changed in 16/27 patients extending the PTV to the lymphatic drainage (10/16), PSMA-positive LR (3/16), bone metastases (2/16) and both nodal/bone metastases (1/16). PET-based increase of primary PTV was 116%. PET-based boosts were administered in 19/27 patients (8/19: local, 10/19: nodal, 1/19: both), median boost volume was 31.3 cm3 (range 17.2-80.2) (local) and 19.7 cm3 (range 3.0-109.3) (nodal). PTV was changed in 1/11 (9%) of dRT patients (extension of primary PTV to the lymphatic drainage (RT volume of 644.5 cm3), additional nodal boost (volume of 2.7 cm3, 23.1 Gy)). All patients showed biochemical response (mean PSA decrease 88.8 +/- 14.0%). Nadir PSA was reached 10 months (range 1-17) after end of RT (median 0.07 ng/ml, range 0.002-3.96). Within a median 12 months follow-up (range 3-22/8-24 in sRT/dRT), median PSA was 0.05 ng/ml (range 0.002-8.5) (sRT) and 0.26 ng/ml (range 0.02-2.68) (dRT). CONCLUSIONS: 68Ga-PSMA PET/CT influenced sRT planning in almost 63% and dRT in 9% of patients by change of PTV and additional boosts.

Multi-modal assessment of a cardiac stem cell therapy reveals distinct modulation of regional scar properties.

BACKGROUND: The initial idea of functional tissue replacement has shifted to the concept that injected cells positively modulate myocardial healing by a non-specific immune response of the transplanted cells within the target tissue. This alleged local modification of the scar requires assessment of regional properties of the left ventricular wall in addition to commonly applied measures of global morphological and functional parameters. Hence, we aimed at investigating the effect of cardiac cell therapy with cardiovascular progenitor cells, so-called cardiac induced cells, on both global and regional properties of the left ventricle by a multimodal imaging approach in a mouse model. METHODS: Myocardial infarction was induced in mice by ligation of the left anterior descending artery, the therapy group received an intramyocardial injection of 1 × 106 cardiac induced cells suspended in matrigel, the control group received matrigel only. [18F]FDG positron emission tomography imaging was performed after 17 days, to assess regional glucose metabolism. Three weeks after myocardial infarction, cardiac magnetic resonance imaging was performed for morphological and functional assessment of the left ventricle. Following these measurements, hearts were excised for histological examinations. RESULTS: Cell therapy had no significant effect on global morphological parameters. Similarly, there was no difference in scar size and capillary density between therapy and control group. However, there was a significant improvement in contractile function of the left ventricle - left ventricular ejection fraction, stroke volume and cardiac output. Regional analysis of the left ventricle identified changes of wall properties in the scar area as the putative mechanism. Cell therapy reduced the thinning of the scar and significantly improved its radial contractility. Furthermore, the metabolic defect, assessed by [18F]FDG, was significantly reduced by the cell therapy. CONCLUSION: Our data support the relevance of extending the assessment of global left ventricular parameters by a structured regional wall analysis for the evaluation of therapies targeting at modulation of healing myocardium. This approach will enable a deeper understanding of mechanisms underlying the effect of experimental regenerative therapies, thus paving the way for a successful translation into clinical application.

Renal and Multiorgan Safety of 177Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer in the VISION Dosimetry Substudy.

In the VISION trial, [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) plus protocol-permitted standard of care significantly improved overall survival and radiographic progression-free survival compared with standard of care alone in patients with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer. This VISION dosimetry substudy quantified absorbed doses of 177Lu-PSMA-617 in the kidneys and other organs. Methods: Participants were a separate cohort of 30 nonrandomized patients receiving standard of care plus 177Lu-PSMA-617 at 7.4 GBq per cycle for up to 6 cycles. Blood samples, whole-body conjugate planar image scintigraphy, and abdominal SPECT/CT images were collected. SPECT/CT images were collected at 2, 24, 48, and 168 h after administration in cycle 1 and at a single time point 48 h after administration in cycles 2-6. Outcomes were absorbed dose per unit activity per cycle and cumulative absorbed dose over all cycles. Cumulative absorbed doses were predicted by extrapolation from cycle 1, and calculation of observed values was based on measurements of cycle 1 and cycles 2-6. Safety was also assessed. Results: Mean (±SD) absorbed doses per cycle in the kidneys were 0.43 ± 0.16 Gy/GBq in cycle 1 and 0.44 ± 0.21 Gy/GBq in cycles 2-6. The observed and predicted 6-cycle cumulative absorbed doses in the kidneys were 15 ± 6 and 19 ± 7 Gy, respectively. Observed and predicted cumulative absorbed doses were similar in other at-risk organs. Safety findings were consistent with those in the VISION study; no patients experienced renal treatment-emergent adverse events of a grade higher than 3. Conclusion: The renal cumulative absorbed 177Lu-PSMA-617 dose was below the established limit. 177Lu-PSMA-617 had a good overall safety profile, and low renal radiotoxicity was not a safety concern. Cumulative absorbed doses in at-risk organs over multiple cycles can be predicted by extrapolation from cycle 1 data in patients with metastatic castration-resistant prostate cancer receiving 177Lu-PSMA-617.

Implementation of dosimetry for molecular radiotherapy; results from a European survey.

PURPOSE: The use of molecular radiotherapy (MRT) has been rapidly evolving over the last years. The aim of this study was to assess the current implementation of dosimetry for MRTs in Europe. METHODS: A web-based questionnaire was open for treating centres between April and June 2022, and focused on 2020-2022. Questions addressed the application of 16 different MRTs, the availability and involvement of medical physicists, software used, quality assurance, as well as the target regions for dosimetry, whether treatment planning and/or verification were performed, and the dosimetric methods used. RESULTS: A total of 173 responses suitable for analysis was received from centres performing MRT, geographically distributed over 27 European countries. Of these, 146 centres (84 %) indicated to perform some form of dosimetry, and 97 % of these centres had a medical physicist available and almost always involved in dosimetry. The most common MRTs were 131I-based treatments for thyroid diseases and thyroid cancer, and [223Ra]RaCl2 for bone metastases. The implementation of dosimetry varied widely between therapies, from almost all centres performing dosimetry-based planning for microsphere treatments to none for some of the less common treatments (like 32P sodium-phosphate for myeloproliferative disease and [89Sr]SrCl2 for bone metastases). CONCLUSIONS: Over the last years, implementation of dosimetry, both for pre-therapeutic treatment planning and post-therapy absorbed dose verification, increased for several treatments, especially for microsphere treatments. For other treatments that have moved from research to clinical routine, the use of dosimetry decreased in recent years. However, there are still large differences both across and within countries.

Preclinical Comparison of the 64Cu- and 68Ga-Labeled GRPR-Targeted Compounds RM2 and AMTG, as Well as First-in-Humans [68Ga]Ga-AMTG PET/CT.

Despite the recent success of prostate-specific membrane antigen (PSMA)-targeted compounds for theranostic use in prostate cancer (PCa), alternative options for the detection and treatment of PSMA-negative lesions are needed. We have recently developed a novel gastrin-releasing peptide receptor (GRPR) ligand with improved metabolic stability, which might improve diagnostic and therapeutic efficacy and could be valuable for PSMA-negative PCa patients. Our aim was to examine its suitability for theranostic use. We performed a comparative preclinical study on [64Cu]Cu-/[68Ga]Ga-AMTG ([64Cu]Cu-/[68Ga]Ga-α-Me-l-Trp8-RM2) using [64Cu]Cu-/[68Ga]Ga-RM2 ([64Cu]Cu-/[68Ga]Ga-DOTA-Pip5-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2) as a reference compound and investigated [68Ga]Ga-AMTG in a proof-of-concept study in a PCa patient. Methods: Peptides were labeled with 64Cu (80 °C, 1.0 M NaOAc, pH 5.50) and 68Ga (90 °C, 0.25 M NaOAc, pH 4.50). GRPR affinity (half-maximal inhibitory concentration, room temperature, 2 h) and GRPR-mediated internalization (37 °C, 60 min) were examined on PC-3 cells. Biodistribution studies were performed at 1 h after injection in PC-3 tumor-bearing mice. For a first-in-humans application, 173 MBq of [68Ga]Ga-AMTG were administered intravenously and whole-body PET/CT scans were acquired at 75 min after injection. Results: 64Cu- and 68Ga-labeling proceeded almost quantitatively (>98%). All compounds revealed similarly high GRPR affinity (half-maximal inhibitory concentration, 1.5-4.0 nM) and high receptor-bound fractions (79%-84% of cell-associated activity). In vivo, high activity levels (percentage injected dose per gram) were found in the PC-3 tumor (14.1-15.1 %ID/g) and the pancreas (12.6-30.7 %ID/g), whereas further off-target accumulation was low at 1 h after injection, except for elevated liver uptake observed for both 64Cu-labeled compounds. Overall biodistribution profiles and tumor-to-background ratios were comparable but slightly enhanced for the 68Ga-labeled analogs in most organs. [68Ga]Ga-AMTG confirmed the favorable pharmacokinetics-as evident from preclinical studies-in a patient with metastasized castration-resistant PCa showing intense uptake in several lesions. Conclusion: AMTG is eligible for theranostic use, as labeling with 64Cu and 68Ga, as well as 177Lu (known from previous study), does not have a negative influence on its favorable biodistribution pattern. For this reason, further clinical evaluation is warranted.

Topical 188Re Ionizing Radiation Therapy Exerts High Efficacy in Curing Nonmelanoma Skin Cancer.

PURPOSE OF THE REPORT: Nonmelanoma skin cancer (NMSC) is the most frequent malignancy. Surgical intervention is the common treatment but may lead to disappointing results; alternative treatment options are needed. METHODS: In this monocentric pilot study, topical 188Re resin was investigated as a treatment for invasive NMSC up to 3-mm thickness. Twenty-two patients with 40 histologically confirmed NMSCs with a median size of 1.25 cm2 (range, 0.04-16.8 cm2) and a median tumor thickness of 0.35 mm (range, 0.1-2.1 mm) were included. Patients were treated once with 188Re resin with a targeted dose of 50 Gy. The median applied activity was 111.4 MBq (range, 21.0-168.0 MBq), and the median treatment time was 89 minutes (range, 38-175 minutes). The response rate, adverse events, and cosmetic outcome were assessed at 14 days, 4 months, and 12 months. RESULTS: Response rate at 12 months was 97.5%, with 95% complete responses (clinically or histologically proven in case of clinical doubt). Most adverse events were reported at 14 days, with 20% itching and 12.5% mostly minor pain. Forty-nine percent of the lesions showed hypopigmentation only at 12 months. Forty-one percent of the lesions were graded as cosmetically superior to the expected result after surgery and 51.3% as comparable to successful surgery. The cosmetic outcome on the head and face was superior compared with the trunk and leg (P = 0.003). CONCLUSION: 188Re resin is a highly effective treatment for NMSC up to 3-mm thickness and a valid alternative to surgery, specifically for tumors located on sensitive areas such as nose or ear.

Patient-related benefits of amyloid PET imaging in dementia: Rationale and design of the German randomized coverage with evidence development study ENABLE.

The utility of amyloid positron emission tomography (PET) for the etiological diagnosis of dementia and its impact on functional status of patients in routine care are currently unclear. Here, we describe the design of ENABLE, a randomized controlled two-armed coverage with evidence development (CED) study in Germany. Approximately 1126 patients with mild to moderate dementia of unclear etiology will be randomly assigned to either an amyloid PET or a no amyloid PET group. Patients will be followed-up for 24 months. The study has been registered at the German Clinical Trials Register (https://drks.de/search/de/trial/DRKS00030839) with the registration code DRKS00030839. The primary endpoint of ENABLE is the ability to perform functional activities of daily living at 18 months. Secondary endpoints include change in diagnosis, diagnostic confidence, and cognitive and clinical outcomes of patients. We expect that the CED study ENABLE will inform about patient relevant effects of amyloid PET in routine care. Furthermore, we anticipate that ENABLE will support physicians' and payers' decisions on provision of health care for patients with dementia. Highlights: Study design focuses on the usefulness of amyloid positron emission tomography (PET) in routine care.Study design addresses the patient-relevant effect of amyloid PET.Patient representatives were involved in the creation of the study design.The study will help improve routine care for people with dementia.

Translational assessment of a DATA-functionalized FAP inhibitor with facile 68Ga-labeling at room temperature.

PURPOSE: The present study aims at evaluating the preclinical and the clinical performance of [68Ga]Ga-DATA5m.SA.FAPi, which has the advantage to be labeled with gallium-68 at room temperature. METHODS: [68Ga]Ga-DATA5m.SA.FAPi was assessed in vitro on FAP-expressing stromal cells, followed by biodistribution and in vivo imaging on prostate and glioblastoma xenografts. Moreover, the clinical assessment of [68Ga]Ga-DATA5m.SA.FAPi was conducted on six patients with prostate cancer, aiming on investigating, biodistribution, biokinetics, and determining tumor uptake. RESULTS: [68Ga]Ga-DATA5m.SA.FAPi is quantitatively prepared in an instant kit-type version at room temperature. It demonstrated high stability in human serum, affinity for FAP in the low nanomolar range, and high internalization rate when associated with CAFs. Biodistribution and PET studies in prostate and glioblastoma xenografts revealed high and specific tumor uptake. Elimination of the radiotracer mainly occurred through the urinary tract. The clinical data are in accordance with the preclinical data concerning the organ receiving the highest absorbed dose (urinary bladder wall, heart wall, spleen, and kidneys). Different to the small-animal data, uptake of [68Ga]Ga-DATA5m.SA.FAPi in tumor lesions is rapid and stable and tumor-to-organ and tumor-to-blood uptake ratios are high. CONCLUSION: The radiochemical, preclinical, and clinical data obtained in this study strongly support further development of [68Ga]Ga-DATA5m.SA.FAPi as a diagnostic tool for FAP imaging.

[18F]GE-180-PET and Post Mortem Marker Characteristics of Long-Term High-Fat-Diet-Induced Chronic Neuroinflammation in Mice.

Obesity is characterized by immoderate fat accumulation leading to an elevated risk of neurodegenerative disorders, along with a host of metabolic disturbances. Chronic neuroinflammation is a main factor linking obesity and the propensity for neurodegenerative disorders. To determine the cerebrometabolic effects of diet-induced obesity (DIO) in female mice fed a long-term (24 weeks) high-fat diet (HFD, 60% fat) compared to a group on a control diet (CD, 20% fat), we used in vivo PET imaging with the radiotracer [18F]FDG as a marker for brain glucose metabolism. In addition, we determined the effects of DIO on cerebral neuroinflammation using translocator protein 18 kDa (TSPO)-sensitive PET imaging with [18F]GE-180. Finally, we performed complementary post mortem histological and biochemical analyses of TSPO and further microglial (Iba1, TMEM119) and astroglial (GFAP) markers as well as cerebral expression analyses of cytokines (e.g., Interleukin (IL)-1ß). We showed the development of a peripheral DIO phenotype, characterized by increased body weight, visceral fat, free triglycerides and leptin in plasma, as well as increased fasted blood glucose levels. Furthermore, we found obesity-associated hypermetabolic changes in brain glucose metabolism in the HFD group. Our main findings with respect to neuroinflammation were that neither [18F]GE-180 PET nor histological analyses of brain samples seem fit to detect the predicted cerebral inflammation response, despite clear evidence of perturbed brain metabolism along with elevated IL-1ß expression. These results could be interpreted as a metabolically activated state in brain-resident immune cells due to a long-term HFD.

[Procedure Guideline for Prostate Cancer Imaging with PSMA-ligand PET/CT]. / DGN-Handlungsempfehlung (S1-Leitlinie) ­ PSMA-Liganden-PET/CT in der Diagnostik des Prostatakarzinoms ­ Stand: 01/2022 ­ AWMF-Registernummer: 031-055.

PSMA-PET/CT for imaging prostate cancer (PC) has spread worldwide since its clinical introduction in 2011. The majority of experiences have been collected for PSMA-PET-imaging of recurrent PC. Data for primary staging of high-risk PC are highly promising. Meanwhile, a plethora of PSMA-ligands are available for clinical use (e. g. 68Ga-PSMA-11, 68Ga-PSMA-I&T, 68Ga-PSMA-617, 18F-DCFBC, 18F-DCFPyL, 18F-PSMA-1007, 18F-rhPSMA-7 and 18F-JK-PSMA-7). However, an official approval is available only for 68Ga-PSMA-11 (approved by the US FDA in 2020) and 18F-DCFPyL (approved by the US FDA in 2021).Recommendations for acquisition times vary from 1-2 h p. i. It has been shown that for the majority of tumour lesions, the contrast in PSMA-PET/CT increases with time. Therefore, additional late imaging can help to clarify unclear findings. PSMA-PET/CT should be performed prior to commencing an androgen deprivation therapy (ADT) since (long term) ADT reduces the visibility of PC lesions. Following injection of PSMA-ligands, hydration and forced diuresis are recommended for PSMA-ligands with primarily excretion via the kidneys in order to increase the visibility of tumour lesions adjacent to the urinary bladder.PSMA-ligands are physiologically taken up in multiple normal organs. For some 18F-labelled PSMA-ligands, presence of unspecific focal bone uptake has been reported. When using these tracers, focal bone uptake without CT-correlate should be interpreted with great caution. Besides prostate cancer, practically all solid tumors express PSMA in their neovasculature thereby taking up PSMA-ligands, although usually at a lower extent compared to PC. Also multiple benign lesions and inflammatory processes (e. g. lymph nodes) take up PSMA-ligands, also usually at lower extent compared to PC.

Siponimod ameliorates metabolic oligodendrocyte injury via the sphingosine-1 phosphate receptor 5.

Multiple sclerosis (MS), an autoimmune-driven, inflammatory demyelinating disease of the central nervous system (CNS), causes irreversible accumulation of neurological deficits to a variable extent. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, immunosuppressive therapies show limited efficacy in secondary progressive MS (SPMS). Although modulation of sphingosine-1 phosphate receptors has proven beneficial during SPMS, the underlying mechanisms are poorly understood. In this project, we followed the hypothesis that siponimod, a sphingosine-1 phosphate receptor modulator, exerts protective effects by direct modulation of glia cell function (i.e., either astrocytes, microglia, or oligodendrocytes). To this end, we used the toxin-mediated, nonautoimmune MS animal model of cuprizone (Cup) intoxication. On the histological level, siponimod ameliorated cuprizone-induced oligodendrocyte degeneration, demyelination, and axonal injury. Protective effects were evident as well using GE180 translocator protein 18-kDa (TSPO) imaging with positron emission tomography (PET)/computed tomography (CT) imaging or next generation sequencing (NGS). Siponimod also ameliorated the cuprizone-induced pathologies in Rag1-deficient mice, demonstrating that the protection is independent of T and B cell modulation. Proinflammatory responses in primary mixed astrocytes/microglia cell cultures were not modulated by siponimod, suggesting that other cell types than microglia and astrocytes are targeted. Of note, siponimod completely lost its protective effects in S1pr5-deficient mice, suggesting direct protection of degenerating oligodendrocytes. Our study demonstrates that siponimod exerts protective effects in the brain in a S1PR5-dependent manner. This finding is not just relevant in the context of MS but in other neuropathologies as well, characterized by a degeneration of the axon-myelin unit.

GRPr Theranostics: Current Status of Imaging and Therapy using GRPr Targeting Radiopharmaceuticals.

Addressing molecular targets, that are overexpressed by various tumor entities, using radiolabeled molecules for a combined diagnostic and therapeutic (theranostic) approach is of increasing interest in oncology. The gastrin-releasing peptide receptor (GRPr), which is part of the bombesin family, has shown to be overexpressed in a variety of tumors, therefore, serving as a promising target for those theranostic applications. A large amount of differently radiolabeled bombesin derivatives addressing the GRPr have been evaluated in the preclinical as well as clinical setting showing fast blood clearance and urinary excretion with selective GRPr-binding. Most of the available studies on GRPr-targeted imaging and therapy have evaluated the theranostic approach in prostate and breast cancer applying bombesin derivatives tagged with the predominantly used theranostic pair of 68Ga/177Lu which is the focus of this review.

Joint EANM, SNMMI, and IAEA Enabling Guide: How to Set up a Theranostics Center.

The theranostics concept using the same target for both imaging and therapy dates back to the middle of the last century, when radioactive iodine was first used to treat thyroid diseases. Since then, radioiodine has become broadly established clinically for diagnostic imaging and therapy of benign and malignant thyroid disease, worldwide. However, only since the approval of SSTR2-targeting theranostics following the NETTER-1 trial in neuroendocrine tumors, and the positive outcome of the VISION trial has theranostics gained substantial attention beyond nuclear medicine. The roll-out of radioligand therapy for treating a high-incidence tumor such as prostate cancer requires the expansion of existing and the establishment of new theranostics centers. Despite wide global variation in the regulatory, financial and medical landscapes, this guide attempts to provide valuable information to enable interested stakeholders to safely initiate and operate theranostic centers. This enabling guide does not intend to answer all possible questions, but rather to serve as an overarching framework for multiple, more detailed future initiatives. It recognizes that there are regional differences in the specifics of regulation of radiation safety, but common elements of best practice valid globally.

Joint EANM, SNMMI and IAEA enabling guide: how to set up a theranostics centre.

The theranostics concept using the same target for both imaging and therapy dates back to the middle of the last century, when radioactive iodine was first used to treat thyroid diseases. Since then, radioiodine has become broadly established clinically for diagnostic imaging and therapy of benign and malignant thyroid disease, worldwide. However, only since the approval of SSTR2-targeting theranostics following the NETTER-1 trial in neuroendocrine tumours and the positive outcome of the VISION trial has theranostics gained substantial attention beyond nuclear medicine. The roll-out of radioligand therapy for treating a high-incidence tumour such as prostate cancer requires the expansion of existing and the establishment of new theranostics centres. Despite wide global variation in the regulatory, financial and medical landscapes, this guide attempts to provide valuable information to enable interested stakeholders to safely initiate and operate theranostics centres. This enabling guide does not intend to answer all possible questions, but rather to serve as an overarching framework for multiple, more detailed future initiatives. It recognizes that there are regional differences in the specifics of regulation of radiation safety, but common elements of best practice valid globally.

Olfactory Bulb D2/D3 Receptor Availability after Intrastriatal Botulinum Neurotoxin-A Injection in a Unilateral 6-OHDA Rat Model of Parkinson's Disease.

Olfactory deficits occur as early non-motor symptoms of idiopathic Parkinson's disease (PD) in humans. The first central relay of the olfactory pathway, the olfactory bulb (OB), depends, among other things, on an intact, functional crosstalk between dopaminergic interneurons and dopamine receptors (D2/D3R). In rats, hemiparkinsonism (hemi-PD) can be induced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB), disrupting dopaminergic neurons of the substantia nigra pars compacta (SNpc). In a previous study, we showed that subsequent injection of botulinum neurotoxin-A (BoNT-A) into the striatum can reverse most of the pathological motor symptoms and normalize the D2/D3R availability. To determine whether this rat model is suitable to explain olfactory deficits that occur in humans with PD, we examined the availability of D2/D3R by longitudinal [18F]fallypride-PET/CT, the density of tyrosine hydroxylase immunoreactivity in the OB, olfactory performance by an orienting odor identification test adapted for rats, and a connectome analysis. PET/CT and immunohistochemical data remained largely unchanged after 6-OHDA lesion in experimental animals, suggesting that outcomes of the 6-OHDA hemi-PD rat model do not completely explain olfactory deficits in humans. However, after subsequent ipsilateral BoNT-A injection into the striatum, a significant 8.5% increase of the D2/D3R availability in the ipsilateral OB and concomitant improvement of olfactory performance were detectable. Based on tract-tracing meta-analysis, we speculate that this may be due to indirect connections between the striatum and the OB.

Early Post-ischemic Brain Glucose Metabolism Is Dependent on Function of TLR2: a Study Using [18F]F-FDG PET-CT in a Mouse Model of Cardiac Arrest and Cardiopulmonary Resuscitation.

PURPOSE: The mammalian brain glucose metabolism is tightly and sensitively regulated. An ischemic brain injury caused by cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) affects cerebral function and presumably also glucose metabolism. The majority of patients who survive CA suffer from cognitive deficits and physical disabilities. Toll-like receptor 2 (TLR2) plays a crucial role in inflammatory response in ischemia and reperfusion (I/R). Since deficiency of TLR2 was associated with increased survival after CA-CPR, in this study, glucose metabolism was measured using non-invasive [18F]F-FDG PET-CT imaging before and early after CA-CPR in a mouse model comparing wild-type (WT) and TLR2-deficient (TLR2-/-) mice. The investigation will evaluate whether FDG-PET could be useful as an additional methodology in assessing prognosis. PROCEDURES: Two PET-CT scans using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]F-FDG) tracer were carried out to measure dynamic glucose metabolism before and early after CPR. To achieve this, anesthetized and ventilated adult female WT and TLR2-/- mice were scanned in PET-CT. After recovery from the baseline scan, the same animals underwent 10-min KCL-induced CA followed by CPR. Approximately 90 min after CA, measurements of [18F]F-FDG uptake for 60 min were started. The [18F]F-FDG standardized uptake values (SUVs) were calculated using PMOD-Software on fused FDG-PET-CT images with the included 3D Mirrione-Mouse-Brain-Atlas. RESULTS: The absolute SUVmean of glucose in the whole brain of WT mice was increased about 25.6% after CA-CPR. In contrast, the absolute glucose SUV in the whole brain of TLR2-/- mice was not significantly different between baseline and measurements post CA-CPR. In comparison, baseline measurements of both mouse strains show a highly significant difference with regard to the absolute glucose SUV in the whole brain. Values of TLR2-/- mice revealed a 34.6% higher glucose uptake. CONCLUSIONS: The altered mouse strains presented a different pattern in glucose uptake under normal and ischemic conditions, whereby the post-ischemic differences in glucose metabolism were associated with the function of key immune factor TLR2. There is evidence for using early FDG-PET-CT as an additional diagnostic tool after resuscitation. Further studies are needed to use PET-CT in predicting neurological outcomes.

Streamlined Schemes for Dosimetry of 177Lu-Labeled PSMA Targeting Radioligands in Therapy of Prostate Cancer.

(Background) Aim of this retrospective analysis was to investigate in mCRPC patients treated with [177Lu]Lu-PSMA-617 whether the absorbed dose (AD) in organs at risk (OAR, i.e., kidneys and parotid glands) can be calculated using simplified methodologies with sufficient accuracy. For this calculation, results and kinetics of the first therapy cycle were used. (Methods) 46 patients treated with 2 to 6 cycles of [177Lu]Lu-PSMA-617 were included. As reference (current clinical standard) full dosimetry of the OAR based on quantitative imaging (whole body scintigraphy and quantitative SPECT/CT at 2, 24, 48 and 72 h p.i.) for every cycle was used. Alternatively, two dosimetry schemes, simplified in terms of image acquisition and dose calculation, were established, both assuming nearly unchanged kinetics of the radiopharmaceutical for subsequent cycles. (Results) In general, for both OAR the simplified methods provided results that were consistent with the dosimetric reference method, both per cycle and in terms of cumulative AD. Best results were obtained when imaging was performed at 48 h p.i. in each of the subsequent cycles. However, both simplified methods tended to underestimate the cumulative AD. (Conclusion) Simplified dosimetry schemes are feasible to tailor multi-cycle [177Lu]Lu-PSMA-targeted therapies.