Publikationen

Nasopharyngeal cancer (NPC), endemic in Southeast Asia, lacks effective diagnostic and therapeutic strategies. Even in high-income countries the 5-year survival rate for stage IV NPC is less than 40%. Here we report high somatostatin receptor 2 (SSTR2) expression in multiple clinical cohorts comprising 402 primary, locally recurrent and metastatic NPCs. We show that SSTR2 expression is induced by the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) via the NF-κB pathway. Using cell-based and preclinical rodent models, we demonstrate the therapeutic potential of SSTR2 targeting using a cytotoxic drug conjugate, PEN-221, which is found to be superior to FDA-approved SSTR2-binding cytostatic agents. Furthermore, we reveal significant correlation of SSTR expression with increased rates of survival and report in vivo uptake of the SSTR2-binding Ga-DOTA-peptide radioconjugate in PET-CT scanning in a clinical trial of NPC patients (NCT03670342). These findings reveal a key role in EBV-associated NPC for SSTR2 in infection, imaging, targeted therapy and survival.

Antifungal resistance of human fungal pathogens represents an increasing challenge in modern medicine. Short antimicrobial peptides (AMP) display a promising class of antifungals with a different mode of action, but lack target specificity and metabolic stability. In this study the hexapeptide PAF26 (Ac-dArg-dLys-dLys-dTrp-dPhe-dTrp-NH2) and the three amino acid long peptide NLF (H2N-Asn-Leu-dPhe-COOH) were coupled to diacetylfusarinine C (DAFC), a derivative of the siderophore triacetylfusarinine C (TAFC) of , to achieve targeted delivery for treatment of invasive aspergillosis. Conjugated compounds in various modifications were labelled with radioactive gallium-68 to perform in vitro and in vivo characterizations. LogD, serum stability, uptake- growth promotion- and minimal inhibitory concentration assays were performed, as well as in vivo stability tests and biodistribution in BALB/c mice. Uptake and growth assays revealed specific internalization of the siderophore conjugates by . They showed a high stability in human serum and also in the blood of BALB/c mice but metabolites in urine, probably due to degradation in the kidneys. Only PAF26 showed growth inhibition at 8 µg/ml which was lost after conjugation to DAFC. Despite their lacking antifungal activity conjugates based on a siderophore scaffold have a potential to provide the basis for a new class of antifungals, which allow the combination of imaging by using PET/CT with targeted treatment, thereby opening a theranostic approach for personalized therapy.

Risk classification of primary prostate cancer in clinical routine is mainly based on prostate-specific antigen (PSA) levels, Gleason scores from biopsy samples, and tumor-nodes-metastasis (TNM) staging. This study aimed to investigate the diagnostic performance of positron emission tomography/magnetic resonance imaging (PET/MRI) in vivo models for predicting low-vs-high lesion risk (LH) as well as biochemical recurrence (BCR) and overall patient risk (OPR) with machine learning.

Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project "TECANT" two Tc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log , protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. [Tc]Tc-TECANT-1 showed higher hydrophilicity and lower protein binding than [Tc]-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while [Tc]Tc-TECANT-1 had higher cellular uptake (>50%, at 2 h/37 °C) and lower dissociation rate (<30%, at 2 h/37 °C). In vivo, [Tc]Tc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to [Tc]Tc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for [Tc]Tc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 µSv/MBq for both radiotracers. This preclinical study provided the basis of selection of [Tc]Tc-TECANT-1 for clinical translation of the first Tc-based SST2 antagonist.

( mutation is an important prognostic factor and a potential therapeutic target in glioma. Immunohistological and molecular diagnosis of mutation status is invasive. To avoid tumor biopsy, dedicated spectroscopic techniques have been proposed to detect D-2-hydroxyglutarate (2-HG), the main metabolite of , directly in vivo. However, these methods are technically challenging and not broadly available. Therefore, we explored the use of machine learning for the non-invasive, inexpensive and fast diagnosis of status in standard H-magnetic resonance spectroscopy (H-MRS). To this end, 30 of 34 consecutive patients with known or suspected glioma WHO grade II-IV were subjected to metabolic positron emission tomography (PET) imaging with O-(2-F-fluoroethyl)-L-tyrosine (F-FET) for optimized voxel placement in H-MRS. Routine H-magnetic resonance (H-MR) spectra of tumor and contralateral healthy brain regions were acquired on a 3 Tesla magnetic resonance (3T-MR) scanner, prior to surgical tumor resection and molecular analysis of status. Since 2-HG spectral signals were too overlapped for reliable discrimination of mutated () and wild-type () glioma, we used a nested cross-validation approach, whereby we trained a linear support vector machine (SVM) on the complete spectral information of the H-MRS data to predict status. Using this approach, we predicted status with an accuracy of 88.2%, a sensitivity of 95.5% (95% CI, 77.2-99.9%) and a specificity of 75.0% (95% CI, 42.9-94.5%), respectively. The area under the curve (AUC) amounted to 0.83. Subsequent ex vivo H-nuclear magnetic resonance (H-NMR) measurements performed on metabolite extracts of resected tumor material (eight specimens) revealed myo-inositol (M-ins) and glycine (Gly) to be the major discriminators of status. We conclude that our approach allows a reliable, non-invasive, fast and cost-effective prediction of status in a standard clinical setting.

Radiochemical conversion is an important term to be included in the "Consensus nomenclature rules for radiopharmaceutical chemistry". Radiochemical conversion should be used to define reaction efficiency by measuring the transformation of components in a crude reaction mixture at a given time, whereas radiochemical yield is better suited to define the efficiency of an entire reaction process including, for example, separation, isolation, filtration, and formulation.

Muscarinic acetylcholine receptors (mAChRs) are a pivotal constituent of the central and peripheral nervous system. Yet, therapeutic and diagnostic applications thereof are hampered by the lack of subtype selective ligands. Within this work, we synthesized and chemically characterized three different stereoisomers of hydrobenzoin esters of arecaidine by NMR, HR-MS, chiral chromatography, and HPLC-logP. All compounds are structurally eligible for carbon-11 labeling and show appropriate stability in Dulbecco's phosphate-buffered saline (DPBS) and F12 cell culture medium. A competitive radioligand binding assay on Chinese hamster ovary cell membranes comprising the human mAChR subtypes M1-M5 showed the highest orthosteric binding affinity for subtype M1 and a strong influence of stereochemistry on binding affinity, which corresponds to in silico molecular docking experiments. K values toward M1 were determined as 99 ± 19 nM, 800 ± 200 nM, and 380 ± 90 nM for the (,)-, (,)-, and racemic (,)-stereoisomer, respectively, highlighting the importance of stereochemical variations in mAChR ligand development. All three stereoisomers were shown to act as antagonists toward mAChR M1 using a Fluo-4 calcium efflux assay. With respect to future positron emission tomography (PET) tracer development, the (,)-isomer appears especially promising as a lead structure due to its highest subtype selectivity and lowest K value.

Lenvatinib has proven efficacy in progressive, radioiodine- (RAI-) refractory thyroid cancer (TC). Dose reductions are commonly performed due to decreased tolerability and adverse effects. This retrospective multicenter study analyzed overall survival (OS) and progression-free survival (PFS) and tolerability in the Austrian patient population treated with lenvatinib.

For PET imaging of mantle cell lymphoma (MCL), [F]FDG (2-deoxy-2-[F]fluoro-D-glucose) is the currently recommended radiotracer, although uptake is variable and bone marrow evaluation is limited. In this prospective study, we evaluated the novel CXCR4 (G-protein-coupled C-X-C chemokine receptor type 4) tracer [Ga]Pentixafor in MCL patients, and compared it to [F]FDG. MCL patients underwent [Ga]Pentixafor-PET/MRI, and, if required for routine purposes, also [F]FDG-PET/MRI, before treatment. PET was evaluated separately for 23 anatomic regions (12 lymph node stations and 11 organs/tissues), using MRI as the main reference standard. Standardized uptake values (SUV and SUV) and tumor-to-background ratios (TBR and TBR) were calculated. General Estimation Equations (GEE) were used to compare [Ga]Pentixafor-PET and [F]FDG-PET sensitivities and positive predictive values (PPV). For bone marrow involvement, where biopsy served as the main reference standard, and splenic involvement, receiver operating characteristic curves were used to determine the optimal SUV and TBR cut-off values, and areas under the curve (AUC) were calculated. Twenty-two MCL patients were included. [Ga]Pentixafor-PET sensitivity (100%) was significantly higher than for [F]FDG-PET (75.2%) (<0.001), and PPV was slightly, but not significantly lower (94.0%.vs. 96.5%; =0.21). SUVs and TBRs were significantly higher for [Ga]Pentixafor-PET than for [F]FDG-PET (<0.001 in all cases); the greatest difference was observed for mean TBR, with 4.9 for [Ga]Pentixafor-PET and 2.0 for [F]FDG-PET. For bone marrow involvement, [Ga]Pentixafor-PET SUV showed an AUC of 0.92; and for splenic involvement, TBR showed an AUC of 0.81. [Ga]Pentixafor-PET may become an alternative to [F]FDG-PET in MCL patients, showing clearly higher detection rates and better tumor-to-background contrast.

Combined F-fluoro-deoxyglucose ([18F]FDG) positron emission tomography and computed tomography ([18F]FDG-PET/CT) is increasingly used for the diagnostic and therapeutic management of hematologic and non-hematologic malignancies. Here, we describe a unique case of a patient presenting with very severe aplastic anemia and a mediastinal mass showing disseminated hypermetabolic lesions of the bones after receiving granulocyte colony-stimulating factor (G-CSF), highly suspicious for disseminated metastatic lesions. A 71-year-old patient presented with a 3 week history of dyspnea and fatigue. Blood tests showed severe pancytopenia and iliac crest bone marrow biopsy revealed an extensively hypoplastic bone marrow. Diagnostic work-up by histology, conventional cytogenetics and flow cytometry confirmed the diagnosis of very severe aplastic anemia. Besides blood transfusions, the patient was treated with G-CSF. Furthermore, computed tomography revealed a suspect mass in the anterior mediastinum, presenting with moderate glucose metabolism in the subsequent [18F]FDG-PET/CT scan. In addition, multiple disseminated and highly metabolic bone lesions of primarily the ribs were detected, suspicious of malignant bone infiltration. Since physiologic bone marrow activation by G-CSF-stimulation could not be ruled out, G-CSF therapy was interrupted to repeat the PET/CT scan 10 days later. On the second [18F]FDG-PET/CT the moderately hypermetabolic mediastinal mass persisted. However, the initially FDG-avid bone lesions almost completely resolved, rendering the diagnosis of G-CSF-induced bone marrow hypermetabolism very likely without the need for further invasive diagnostic procedures. The mediastinal mass was thereafter histologically verified as thymoma. Interpretation of [18F]FDG-PET/CT in patients with aplastic anemia may be complicated by the frequent therapeutic use of G-CSF. With G-CSF, islets of residual bone marrow activity can be visualized on [18F]FDG-PET/CT images that might be misinterpreted as malignant bone infiltration. Repeating PET/CT scan after G-CSF discontinuation can prevent unnecessary invasive diagnostic procedures in these patients.