Hier finden Sie die aktuellsten Publikationen aus dem Gebiet der Nuklearmedizin in Österreich. Zusätzlich sind die Publikationen aus den Teilbereichen der PET, SPECT sowie nuklearmedizinischen Therapien unserer Kollegen in Österreich gesondert hervorgehoben.
Rezente Publikationen in Österreich
Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy
Lechner M, Schartinger VH, Steele CD, Nei WL, Ooft ML, Schreiber LM, Pipinikas CP, Chung GT, Chan YY, Wu F, To KF, Tsang CM, Pearce W, Morelli D, Philpott M, Masterson L, Nibhani R, Wells G, Bell CG, Koller J, Delecluse S, Yip YL, Liu J, Forde CT, Forster MD, Jay A, Dudás J, Krapp A, Wan S, Uprimny C, Sprung S, Haybaeck J, Fenton TR, Chester K, Thirlwell C, Royle G, Marafioti T, Gupta R, Indrasari SR, Herdini C, Slim MAM, Indrawati I, Sutton L, Fles R, Tan B, Yeong J, Jain A, Han S, Wang H, Loke KSH, He W, Xu R, Jin H, Cheng Z, Howard D, Hwang PH, Le QT, Tay JK, West RB, Tsao SW, Meyer T, Riechelmann H, Oppermann U, Delecluse HJ, Willems SM, Chua MLK, Busson P, Lo KW, Wollmann G, Pillay N, Vanhaesebroeck B and Lund VJ
Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy
Lechner M, Schartinger VH, Steele CD, Nei WL, Ooft ML, Schreiber LM, Pipinikas CP, Chung GT, Chan YY, Wu F, To KF, Tsang CM, Pearce W, Morelli D, Philpott M, Masterson L, Nibhani R, Wells G, Bell CG, Koller J, Delecluse S, Yip YL, Liu J, Forde CT, Forster MD, Jay A, Dudás J, Krapp A, Wan S, Uprimny C, Sprung S, Haybaeck J, Fenton TR, Chester K, Thirlwell C, Royle G, Marafioti T, Gupta R, Indrasari SR, Herdini C, Slim MAM, Indrawati I, Sutton L, Fles R, Tan B, Yeong J, Jain A, Han S, Wang H, Loke KSH, He W, Xu R, Jin H, Cheng Z, Howard D, Hwang PH, Le QT, Tay JK, West RB, Tsao SW, Meyer T, Riechelmann H, Oppermann U, Delecluse HJ, Willems SM, Chua MLK, Busson P, Lo KW, Wollmann G, Pillay N, Vanhaesebroeck B and Lund VJ
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.
Siderophore Scaffold as Carrier for Antifungal Peptides in Therapy of Infections
Pfister J, Bata R, Hubmann I, Hörmann AA, Gsaller F, Haas H and Decristoforo C
Siderophore Scaffold as Carrier for Antifungal Peptides in Therapy of Infections
Pfister J, Bata R, Hubmann I, Hörmann AA, Gsaller F, Haas H and Decristoforo C
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.
Supervised machine learning enables non-invasive lesion characterization in primary prostate cancer with [Ga]Ga-PSMA-11 PET/MRI
Papp L, Spielvogel CP, Grubmüller B, Grahovac M, Krajnc D, Ecsedi B, Sareshgi RAM, Mohamad D, Hamboeck M, Rausch I, Mitterhauser M, Wadsak W, Haug AR, Kenner L, Mazal P, Susani M, Hartenbach S, Baltzer P, Helbich TH, Kramer G, Shariat SF, Beyer T, Hartenbach M and Hacker M
Supervised machine learning enables non-invasive lesion characterization in primary prostate cancer with [Ga]Ga-PSMA-11 PET/MRI
Papp L, Spielvogel CP, Grubmüller B, Grahovac M, Krajnc D, Ecsedi B, Sareshgi RAM, Mohamad D, Hamboeck M, Rausch I, Mitterhauser M, Wadsak W, Haug AR, Kenner L, Mazal P, Susani M, Hartenbach S, Baltzer P, Helbich TH, Kramer G, Shariat SF, Beyer T, Hartenbach M and Hacker M
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.
Selection of the First Tc-Labelled Somatostatin Receptor Subtype 2 Antagonist for Clinical Translation-Preclinical Assessment of Two Optimized Candidates
Fani M, Weingaertner V, Kolenc Peitl P, Mansi R, Gaonkar RH, Garnuszek P, Mikolajczak R, Novak D, Simoncic U, Hubalewska-Dydejczyk A, Rangger C, Kaeopookum P and Decristoforo C
Selection of the First Tc-Labelled Somatostatin Receptor Subtype 2 Antagonist for Clinical Translation-Preclinical Assessment of Two Optimized Candidates
Fani M, Weingaertner V, Kolenc Peitl P, Mansi R, Gaonkar RH, Garnuszek P, Mikolajczak R, Novak D, Simoncic U, Hubalewska-Dydejczyk A, Rangger C, Kaeopookum P and Decristoforo C
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.
Non-Invasive Prediction of Mutation in Patients with Glioma WHO II/III/IV Based on F-18-FET PET-Guided In Vivo H-Magnetic Resonance Spectroscopy and Machine Learning
Bumes E, Wirtz FP, Fellner C, Grosse J, Hellwig D, Oefner PJ, Häckl M, Linker R, Proescholdt M, Schmidt NO, Riemenschneider MJ, Samol C, Rosengarth K, Wendl C, Hau P, Gronwald W and Hutterer M
Non-Invasive Prediction of Mutation in Patients with Glioma WHO II/III/IV Based on F-18-FET PET-Guided In Vivo H-Magnetic Resonance Spectroscopy and Machine Learning
Bumes E, Wirtz FP, Fellner C, Grosse J, Hellwig D, Oefner PJ, Häckl M, Linker R, Proescholdt M, Schmidt NO, Riemenschneider MJ, Samol C, Rosengarth K, Wendl C, Hau P, Gronwald W and Hutterer M
( 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.
On the consensus nomenclature rules for radiopharmaceutical chemistry - Reconsideration of radiochemical conversion
Herth MM, Ametamey S, Antuganov D, Bauman A, Berndt M, Brooks AF, Bormans G, Choe YS, Gillings N, Häfeli UO, James ML, Kopka K, Kramer V, Krasikova R, Madsen J, Mu L, Neumaier B, Piel M, Rösch F, Ross T, Schibli R, Scott PJH, Shalgunov V, Vasdev N, Wadsak W and Zeglis BM
On the consensus nomenclature rules for radiopharmaceutical chemistry - Reconsideration of radiochemical conversion
Herth MM, Ametamey S, Antuganov D, Bauman A, Berndt M, Brooks AF, Bormans G, Choe YS, Gillings N, Häfeli UO, James ML, Kopka K, Kramer V, Krasikova R, Madsen J, Mu L, Neumaier B, Piel M, Rösch F, Ross T, Schibli R, Scott PJH, Shalgunov V, Vasdev N, Wadsak W and Zeglis BM
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.
Synthesis, Biological, and Computational Evaluation of Antagonistic, Chiral Hydrobenzoin Esters of Arecaidine Targeting mAChR M1
Ozenil M, Aronow J, Piljak D, Vraka C, Holzer W, Spreitzer H, Wadsak W, Hacker M and Pichler V
Synthesis, Biological, and Computational Evaluation of Antagonistic, Chiral Hydrobenzoin Esters of Arecaidine Targeting mAChR M1
Ozenil M, Aronow J, Piljak D, Vraka C, Holzer W, Spreitzer H, Wadsak W, Hacker M and Pichler V
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.
Real-World Data for Lenvatinib in Radioiodine-Refractory Differentiated Thyroid Cancer (RELEVANT): A Retrospective Multicentric Analysis of Clinical Practice in Austria
Rendl G, Sipos B, Becherer A, Sorko S, Trummer C, Raderer M, Hitzl W, Ardelt M, Gallowitsch HJ and Pirich C
Real-World Data for Lenvatinib in Radioiodine-Refractory Differentiated Thyroid Cancer (RELEVANT): A Retrospective Multicentric Analysis of Clinical Practice in Austria
Rendl G, Sipos B, Becherer A, Sorko S, Trummer C, Raderer M, Hitzl W, Ardelt M, Gallowitsch HJ and Pirich C
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.
CXCR4 PET imaging of mantle cell lymphoma using [Ga]Pentixafor: comparison with [F]FDG-PET
Mayerhoefer ME, Raderer M, Lamm W, Pichler V, Pfaff S, Weber M, Kiesewetter B, Hacker M, Kazianka L, Staber PB, Wester HJ, Rohrbeck J, Simonitsch-Klupp I and Haug A
CXCR4 PET imaging of mantle cell lymphoma using [Ga]Pentixafor: comparison with [F]FDG-PET
Mayerhoefer ME, Raderer M, Lamm W, Pichler V, Pfaff S, Weber M, Kiesewetter B, Hacker M, Kazianka L, Staber PB, Wester HJ, Rohrbeck J, Simonitsch-Klupp I and Haug A
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.
Disseminated focal F-fluoro-deoxyglucose uptake upon granulocyte colony-stimulating factor therapy mimicking malignant bone infiltration: case report of a patient with very severe aplastic anemia
Horvath L, Seeber A, Uprimny C, Wolf D, Nachbaur D and Kocher F
Disseminated focal F-fluoro-deoxyglucose uptake upon granulocyte colony-stimulating factor therapy mimicking malignant bone infiltration: case report of a patient with very severe aplastic anemia
Horvath L, Seeber A, Uprimny C, Wolf D, Nachbaur D and Kocher F
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.
Teilbereich PET
Assessment of Central Nervous System Lymphoma Based on CXCR4 Expression In Vivo Using 68Ga-Pentixafor PET/MRI
Starzer AM, Berghoff AS, Traub-Weidinger T, Haug AR, Widhalm G, Hacker M, Rausch I, Preusser M and Mayerhoefer ME
Assessment of Central Nervous System Lymphoma Based on CXCR4 Expression In Vivo Using 68Ga-Pentixafor PET/MRI
Starzer AM, Berghoff AS, Traub-Weidinger T, Haug AR, Widhalm G, Hacker M, Rausch I, Preusser M and Mayerhoefer ME
F-FDG PET is limited for assessment of central nervous system lymphoma (CNSL) due to physiologic tracer accumulation in the brain. We prospectively evaluated the novel PET tracer Ga-pentixafor, which targets the C-X-C chemokine receptor 4 (CXCR4), for lesion visualization and response assessment of CNSL.
Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy
Lechner M, Schartinger VH, Steele CD, Nei WL, Ooft ML, Schreiber LM, Pipinikas CP, Chung GT, Chan YY, Wu F, To KF, Tsang CM, Pearce W, Morelli D, Philpott M, Masterson L, Nibhani R, Wells G, Bell CG, Koller J, Delecluse S, Yip YL, Liu J, Forde CT, Forster MD, Jay A, Dudás J, Krapp A, Wan S, Uprimny C, Sprung S, Haybaeck J, Fenton TR, Chester K, Thirlwell C, Royle G, Marafioti T, Gupta R, Indrasari SR, Herdini C, Slim MAM, Indrawati I, Sutton L, Fles R, Tan B, Yeong J, Jain A, Han S, Wang H, Loke KSH, He W, Xu R, Jin H, Cheng Z, Howard D, Hwang PH, Le QT, Tay JK, West RB, Tsao SW, Meyer T, Riechelmann H, Oppermann U, Delecluse HJ, Willems SM, Chua MLK, Busson P, Lo KW, Wollmann G, Pillay N, Vanhaesebroeck B and Lund VJ
Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy
Lechner M, Schartinger VH, Steele CD, Nei WL, Ooft ML, Schreiber LM, Pipinikas CP, Chung GT, Chan YY, Wu F, To KF, Tsang CM, Pearce W, Morelli D, Philpott M, Masterson L, Nibhani R, Wells G, Bell CG, Koller J, Delecluse S, Yip YL, Liu J, Forde CT, Forster MD, Jay A, Dudás J, Krapp A, Wan S, Uprimny C, Sprung S, Haybaeck J, Fenton TR, Chester K, Thirlwell C, Royle G, Marafioti T, Gupta R, Indrasari SR, Herdini C, Slim MAM, Indrawati I, Sutton L, Fles R, Tan B, Yeong J, Jain A, Han S, Wang H, Loke KSH, He W, Xu R, Jin H, Cheng Z, Howard D, Hwang PH, Le QT, Tay JK, West RB, Tsao SW, Meyer T, Riechelmann H, Oppermann U, Delecluse HJ, Willems SM, Chua MLK, Busson P, Lo KW, Wollmann G, Pillay N, Vanhaesebroeck B and Lund VJ
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.
Siderophore Scaffold as Carrier for Antifungal Peptides in Therapy of Infections
Pfister J, Bata R, Hubmann I, Hörmann AA, Gsaller F, Haas H and Decristoforo C
Siderophore Scaffold as Carrier for Antifungal Peptides in Therapy of Infections
Pfister J, Bata R, Hubmann I, Hörmann AA, Gsaller F, Haas H and Decristoforo C
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.
Supervised machine learning enables non-invasive lesion characterization in primary prostate cancer with [Ga]Ga-PSMA-11 PET/MRI
Papp L, Spielvogel CP, Grubmüller B, Grahovac M, Krajnc D, Ecsedi B, Sareshgi RAM, Mohamad D, Hamboeck M, Rausch I, Mitterhauser M, Wadsak W, Haug AR, Kenner L, Mazal P, Susani M, Hartenbach S, Baltzer P, Helbich TH, Kramer G, Shariat SF, Beyer T, Hartenbach M and Hacker M
Supervised machine learning enables non-invasive lesion characterization in primary prostate cancer with [Ga]Ga-PSMA-11 PET/MRI
Papp L, Spielvogel CP, Grubmüller B, Grahovac M, Krajnc D, Ecsedi B, Sareshgi RAM, Mohamad D, Hamboeck M, Rausch I, Mitterhauser M, Wadsak W, Haug AR, Kenner L, Mazal P, Susani M, Hartenbach S, Baltzer P, Helbich TH, Kramer G, Shariat SF, Beyer T, Hartenbach M and Hacker M
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.
Non-Invasive Prediction of Mutation in Patients with Glioma WHO II/III/IV Based on F-18-FET PET-Guided In Vivo H-Magnetic Resonance Spectroscopy and Machine Learning
Bumes E, Wirtz FP, Fellner C, Grosse J, Hellwig D, Oefner PJ, Häckl M, Linker R, Proescholdt M, Schmidt NO, Riemenschneider MJ, Samol C, Rosengarth K, Wendl C, Hau P, Gronwald W and Hutterer M
Non-Invasive Prediction of Mutation in Patients with Glioma WHO II/III/IV Based on F-18-FET PET-Guided In Vivo H-Magnetic Resonance Spectroscopy and Machine Learning
Bumes E, Wirtz FP, Fellner C, Grosse J, Hellwig D, Oefner PJ, Häckl M, Linker R, Proescholdt M, Schmidt NO, Riemenschneider MJ, Samol C, Rosengarth K, Wendl C, Hau P, Gronwald W and Hutterer M
( 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.
On the consensus nomenclature rules for radiopharmaceutical chemistry - Reconsideration of radiochemical conversion
Herth MM, Ametamey S, Antuganov D, Bauman A, Berndt M, Brooks AF, Bormans G, Choe YS, Gillings N, Häfeli UO, James ML, Kopka K, Kramer V, Krasikova R, Madsen J, Mu L, Neumaier B, Piel M, Rösch F, Ross T, Schibli R, Scott PJH, Shalgunov V, Vasdev N, Wadsak W and Zeglis BM
On the consensus nomenclature rules for radiopharmaceutical chemistry - Reconsideration of radiochemical conversion
Herth MM, Ametamey S, Antuganov D, Bauman A, Berndt M, Brooks AF, Bormans G, Choe YS, Gillings N, Häfeli UO, James ML, Kopka K, Kramer V, Krasikova R, Madsen J, Mu L, Neumaier B, Piel M, Rösch F, Ross T, Schibli R, Scott PJH, Shalgunov V, Vasdev N, Wadsak W and Zeglis BM
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.
Synthesis, Biological, and Computational Evaluation of Antagonistic, Chiral Hydrobenzoin Esters of Arecaidine Targeting mAChR M1
Ozenil M, Aronow J, Piljak D, Vraka C, Holzer W, Spreitzer H, Wadsak W, Hacker M and Pichler V
Synthesis, Biological, and Computational Evaluation of Antagonistic, Chiral Hydrobenzoin Esters of Arecaidine Targeting mAChR M1
Ozenil M, Aronow J, Piljak D, Vraka C, Holzer W, Spreitzer H, Wadsak W, Hacker M and Pichler V
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.
Real-World Data for Lenvatinib in Radioiodine-Refractory Differentiated Thyroid Cancer (RELEVANT): A Retrospective Multicentric Analysis of Clinical Practice in Austria
Rendl G, Sipos B, Becherer A, Sorko S, Trummer C, Raderer M, Hitzl W, Ardelt M, Gallowitsch HJ and Pirich C
Real-World Data for Lenvatinib in Radioiodine-Refractory Differentiated Thyroid Cancer (RELEVANT): A Retrospective Multicentric Analysis of Clinical Practice in Austria
Rendl G, Sipos B, Becherer A, Sorko S, Trummer C, Raderer M, Hitzl W, Ardelt M, Gallowitsch HJ and Pirich C
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.
CXCR4 PET imaging of mantle cell lymphoma using [Ga]Pentixafor: comparison with [F]FDG-PET
Mayerhoefer ME, Raderer M, Lamm W, Pichler V, Pfaff S, Weber M, Kiesewetter B, Hacker M, Kazianka L, Staber PB, Wester HJ, Rohrbeck J, Simonitsch-Klupp I and Haug A
CXCR4 PET imaging of mantle cell lymphoma using [Ga]Pentixafor: comparison with [F]FDG-PET
Mayerhoefer ME, Raderer M, Lamm W, Pichler V, Pfaff S, Weber M, Kiesewetter B, Hacker M, Kazianka L, Staber PB, Wester HJ, Rohrbeck J, Simonitsch-Klupp I and Haug A
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.
Disseminated focal F-fluoro-deoxyglucose uptake upon granulocyte colony-stimulating factor therapy mimicking malignant bone infiltration: case report of a patient with very severe aplastic anemia
Horvath L, Seeber A, Uprimny C, Wolf D, Nachbaur D and Kocher F
Disseminated focal F-fluoro-deoxyglucose uptake upon granulocyte colony-stimulating factor therapy mimicking malignant bone infiltration: case report of a patient with very severe aplastic anemia
Horvath L, Seeber A, Uprimny C, Wolf D, Nachbaur D and Kocher F
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.
Teilbereich SPECT
Selection of the First Tc-Labelled Somatostatin Receptor Subtype 2 Antagonist for Clinical Translation-Preclinical Assessment of Two Optimized Candidates
Fani M, Weingaertner V, Kolenc Peitl P, Mansi R, Gaonkar RH, Garnuszek P, Mikolajczak R, Novak D, Simoncic U, Hubalewska-Dydejczyk A, Rangger C, Kaeopookum P and Decristoforo C
Selection of the First Tc-Labelled Somatostatin Receptor Subtype 2 Antagonist for Clinical Translation-Preclinical Assessment of Two Optimized Candidates
Fani M, Weingaertner V, Kolenc Peitl P, Mansi R, Gaonkar RH, Garnuszek P, Mikolajczak R, Novak D, Simoncic U, Hubalewska-Dydejczyk A, Rangger C, Kaeopookum P and Decristoforo C
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.
Clinical and gated SPECT MPI parameters associated with super-response to cardiac resynchronization therapy
Mesquita CT, Peix A, de Amorim Fernandes F, Giubbini R, Karthikeyan G, Massardo T, Patel C, Pabon LM, Jimenez-Heffernan A, Alexanderson E, Butt S, Kumar A, Marin V, Morozova O, Paez D and Garcia EV
Clinical and gated SPECT MPI parameters associated with super-response to cardiac resynchronization therapy
Mesquita CT, Peix A, de Amorim Fernandes F, Giubbini R, Karthikeyan G, Massardo T, Patel C, Pabon LM, Jimenez-Heffernan A, Alexanderson E, Butt S, Kumar A, Marin V, Morozova O, Paez D and Garcia EV
We sought to evaluate the behavior of cardiac mechanical synchrony as measured by phase SD (PSD) derived from gated MPI SPECT (gSPECT) in patients with super-response after CRT and to evaluate the clinical and imaging characteristics associated with super-response.
Intraventricular synchronism assessment by gated-SPECT myocardial perfusion imaging in cardiac resynchronization therapy. Does cardiomyopathy type influence results?
Peix A, Padrón K, Cabrera LO, Castañeda O, Milán D, Castro J, Falcón R, Martínez F, Rodríguez L, Sánchez J, Mena E, Carrillo R, Fernández Y, Escarano R, Páez D and Dondi M
Intraventricular synchronism assessment by gated-SPECT myocardial perfusion imaging in cardiac resynchronization therapy. Does cardiomyopathy type influence results?
Peix A, Padrón K, Cabrera LO, Castañeda O, Milán D, Castro J, Falcón R, Martínez F, Rodríguez L, Sánchez J, Mena E, Carrillo R, Fernández Y, Escarano R, Páez D and Dondi M
To analyze the evolution post-cardiac resynchronization therapy (CRT) in left ventricular non-compaction (LVNC) cardiomyopathy (CM) patients compared to other types of CM, according to clinical and functional variables, by using gated-SPECT myocardial perfusion imaging (MPI).
Reproducibility of global LV function and dyssynchrony parameters derived from phase analysis of gated myocardial perfusion SPECT: A multicenter comparison with core laboratory setting
de Amorim Fernandes F, Peix A, Giubbini R, Karthikeyan G, Massardo T, Patel C, Pabon LM, Jimenez-Heffernan A, Alexanderson E, Butt S, Kumar A, Marin V, Morozova O, Paez D, Mesquita CT and Garcia EV
Reproducibility of global LV function and dyssynchrony parameters derived from phase analysis of gated myocardial perfusion SPECT: A multicenter comparison with core laboratory setting
de Amorim Fernandes F, Peix A, Giubbini R, Karthikeyan G, Massardo T, Patel C, Pabon LM, Jimenez-Heffernan A, Alexanderson E, Butt S, Kumar A, Marin V, Morozova O, Paez D, Mesquita CT and Garcia EV
Gated myocardial perfusion scintigraphy (GMPS) phase analysis is an important tool to investigate the physiology of left ventricular (LV) dyssynchrony. We aimed to test the performance of GMPS LV function and phase analysis in different clinical settings and on a diverse population.
In Vivo Quantification of Myocardial Amyloid Deposits in Patients with Suspected Transthyretin-Related Amyloidosis (ATTR)
Wollenweber T, Rettl R, Kretschmer-Chott E, Rasul S, Kulterer O, Rainer E, Raidl M, Schaffarich MP, Matschitsch S, Stadler M, Traub-Weidinger T, Beiztke D, Loewe C, Duca F, Mascherbauer J, Bonderman D and Hacker M
In Vivo Quantification of Myocardial Amyloid Deposits in Patients with Suspected Transthyretin-Related Amyloidosis (ATTR)
Wollenweber T, Rettl R, Kretschmer-Chott E, Rasul S, Kulterer O, Rainer E, Raidl M, Schaffarich MP, Matschitsch S, Stadler M, Traub-Weidinger T, Beiztke D, Loewe C, Duca F, Mascherbauer J, Bonderman D and Hacker M
Current diagnosis of Transthyretin-related Amyloidosis (ATTR) using bone scintigraphy is primarily based on visual scoring and semi-quantitative indices. With the introduction of new potential life-prolonging drugs for ATTR, a more precise quantification of myocardial amyloid burden is desirable for improved response prediction and therapy monitoring.
Prognostic value of ventricular mechanical dyssynchrony in patients with left ventricular aneurysm: A comparative study of medical and surgical treatment
Lu X, Zhao M, Tian C, Wei H, Gao M, Yang X, Zhang X and Li X
Prognostic value of ventricular mechanical dyssynchrony in patients with left ventricular aneurysm: A comparative study of medical and surgical treatment
Lu X, Zhao M, Tian C, Wei H, Gao M, Yang X, Zhang X and Li X
The prognostic value of left ventricular (LV) mechanical dyssynchrony (MD) in patients with LV aneurysm (LVA) is unclear. This study aimed to investigate the long-term prognostic value of LVMD in LVA patients.
Worldwide Diagnostic Reference Levels for Single-Photon Emission Computed Tomography Myocardial Perfusion Imaging: Findings From INCAPS
Hirschfeld CB, Dondi M, Pascual TNB, Mercuri M, Vitola J, Karthikeyan G, Better N, Mahmarian JJ, Bouyoucef SE, Hee-Seung Bom H, Lele V, Magboo VPC, Alexánderson E, Allam AH, Al-Mallah MH, Flotats A, Jerome S, Kaufmann PA, Luxenburg O, Underwood SR, Rehani MM, Vassileva J, Paez D, Einstein AJ and
Worldwide Diagnostic Reference Levels for Single-Photon Emission Computed Tomography Myocardial Perfusion Imaging: Findings From INCAPS
Hirschfeld CB, Dondi M, Pascual TNB, Mercuri M, Vitola J, Karthikeyan G, Better N, Mahmarian JJ, Bouyoucef SE, Hee-Seung Bom H, Lele V, Magboo VPC, Alexánderson E, Allam AH, Al-Mallah MH, Flotats A, Jerome S, Kaufmann PA, Luxenburg O, Underwood SR, Rehani MM, Vassileva J, Paez D, Einstein AJ and
This study sought to establish worldwide and regional diagnostic reference levels (DRLs) and achievable administered activities (AAAs) for single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI).
Myocardial F-FDG Uptake Pattern for Cardiovascular Risk Stratification in Patients Undergoing Oncologic PET/CT
Haider A, Bengs S, Schade K, Wijnen WJ, Portmann A, Etter D, Fröhlich S, Warnock GI, Treyer V, Burger IA, Fiechter M, Kudura K, Fuchs TA, Pazhenkottil AP, Buechel RR, Kaufmann PA, Meisel A, Stolzmann P and Gebhard C
Myocardial F-FDG Uptake Pattern for Cardiovascular Risk Stratification in Patients Undergoing Oncologic PET/CT
Haider A, Bengs S, Schade K, Wijnen WJ, Portmann A, Etter D, Fröhlich S, Warnock GI, Treyer V, Burger IA, Fiechter M, Kudura K, Fuchs TA, Pazhenkottil AP, Buechel RR, Kaufmann PA, Meisel A, Stolzmann P and Gebhard C
Positron emission tomography/computed tomography with F-fluorodeoxy-glucose (F-FDG-PET/CT) has become the standard staging modality in various tumor entities. Cancer patients frequently receive cardio-toxic therapies. However, routine cardiovascular assessment in oncologic patients is not performed in current clinical practice. Accordingly, this study sought to assess whether myocardial F-FDG uptake patterns of patients undergoing oncologic PET/CT can be used for cardiovascular risk stratification.
Cu-DOTATOC PET-CT in Patients with Neuroendocrine Tumors
Mirzaei S, Revheim ME, Raynor W, Zehetner W, Knoll P, Zandieh S and Alavi A
Cu-DOTATOC PET-CT in Patients with Neuroendocrine Tumors
Mirzaei S, Revheim ME, Raynor W, Zehetner W, Knoll P, Zandieh S and Alavi A
Several radiolabeled somatostatin analogues have been developed for molecular imaging of neuroendocrine tumors (NETs) with single-photon emission computed tomography (SPECT) and positron-emission tomography (PET). The aim of the present study was to report our first results using Cu-DOTATOC in patients with NETs.
Radionuclide Imaging for Neuroscience: Current Opinion and Future Directions
Gee AD, Herth MM, James ML, Korde A, Scott PJH and Vasdev N
Radionuclide Imaging for Neuroscience: Current Opinion and Future Directions
Gee AD, Herth MM, James ML, Korde A, Scott PJH and Vasdev N
This meeting report summarizes a Consultants Meeting that was held at International Atomic Energy Agency headquarters in Vienna to provide an update on radionuclide imaging for neuroscience applications.
Teilbereich Nuklearmedizinische Therapie
Dose Calculations and Dose-Effect Relationships in 177Lu-PSMA I&T Radionuclide Therapy for Metastatic Castration-Resistant Prostate Cancer
Barna S, Haug AR, Hartenbach M, Rasul S, Grubmüller B, Kramer G and Blaickner M
Dose Calculations and Dose-Effect Relationships in 177Lu-PSMA I&T Radionuclide Therapy for Metastatic Castration-Resistant Prostate Cancer
Barna S, Haug AR, Hartenbach M, Rasul S, Grubmüller B, Kramer G and Blaickner M
Dose response of 22 patients experiencing mCRPC (metastatic castration-resistant prostate cancer) to Lu-PSMA I&T radionuclide therapy was investigated. Dosimetry calculations are used to assess correlations between dosimetric quantities and biomarker values.
Theranostics of Metastatic Prostate Cancer Applying 64Cu/18F/68Ga PSMA PET-CT and 177Lu Radiopharmaceuticals
Mirzaei S, Mohammed F and Zandieh S
Theranostics of Metastatic Prostate Cancer Applying 64Cu/18F/68Ga PSMA PET-CT and 177Lu Radiopharmaceuticals
Mirzaei S, Mohammed F and Zandieh S
The successful use of theranostic twins in neuroendocrine tumors (NET) was the pioneering approach to radionuclide therapy in other tumor types. 64Cu/18F PSMA for molecular imaging with PET-CT and peptide radioligand therapy (PRLT) with 177Lu labeled PSMA inhibitors are the next theranostic twins in nuclear medicine. 68Ga/ 64Cu/18F PSMA PET-CT detects metastatic prostate cancer with high diagnostic sensitivity and specificity and can be used to select patients for PRLT and evaluate therapy response. Radionuclide therapy with 177Lu-PSMA inhibitors has been shown to be effective in the treatment of metastatic CRPC.
Targeted Palliative Radionuclide Therapy for Metastatic Bone Pain
Manafi-Farid R, Masoumi F, Divband G, Saidi B, Ataeinia B, Hertel F, Schweighofer-Zwink G, Morgenroth A and Beheshti M
Targeted Palliative Radionuclide Therapy for Metastatic Bone Pain
Manafi-Farid R, Masoumi F, Divband G, Saidi B, Ataeinia B, Hertel F, Schweighofer-Zwink G, Morgenroth A and Beheshti M
Bone metastasis develops in multiple malignancies with a wide range of incidence. The presence of multiple bone metastases, leading to a multitude of complications and poorer prognosis. The corresponding refractory bone pain is still a challenging issue managed through multidisciplinary approaches to enhance the quality of life. Radiopharmaceuticals are mainly used in the latest courses of the disease. Bone-pain palliation with easy-to-administer radionuclides offers advantages, including simultaneous treatment of multiple metastatic foci, the repeatability and also the combination with other therapies. Several β¯- and α-emitters as well as pharmaceuticals, from the very first [Sr]strontium-dichloride to recently introduced [Ra]radium-dichloride, are investigated to identify an optimum agent. In addition, the combination of bone-seeking radiopharmaceuticals with chemotherapy or radiotherapy has been employed to enhance the outcome. Radiopharmaceuticals demonstrate an acceptable response rate in pain relief. Nevertheless, survival benefits have been documented in only a limited number of studies. In this review, we provide an overview of bone-seeking radiopharmaceuticals used for bone-pain palliation, their effectiveness and toxicity, as well as the results of the combination with other therapies. Bone-pain palliation with radiopharmaceuticals has been employed for eight decades. However, there are still new aspects yet to be established.
How I treat neuroendocrine tumours
Kiesewetter B and Raderer M
How I treat neuroendocrine tumours
Kiesewetter B and Raderer M
Neuroendocrine tumours (NETs) constitute a heterogeneous group of neoplasms characterised by variable endocrine activity and somatostatin receptor expression, with the latter allowing the use of targeted therapeutic concepts. Currently accepted treatment strategies for advanced well-differentiated NET include somatostatin analogues octreotide and lanreotide, peptide receptor radionuclide therapy using radiolabelled somatostatin analogues, mammalian target of Rapamycin inhibitor everolimus, tyrosine kinase inhibitor sunitinib, interferon alpha and classical cytostatic, such as streptozotocin-based and temozolomide-based treatment. Indication, use and approval of these treatments differ based on primary tumour origin, grading and symptomatic burden and require an optimised multidisciplinary cooperation of medical oncologists, endocrinologists and nuclear medicine specialists. Interestingly, hot topics in oncology including immunotherapy and use of next-generation-sequencing techniques currently play a minor role for the treatment of NETs. The recent revision of the WHO classification including the recognition of the novel NET G3 category allows for potentially more tailored treatment strategies in the near future. However, this new entity also poses a therapeutic challenge as only limited data are currently available. The present article aims to provide an overview on our personal treatment concepts for advanced NETs with a focus on tumours of gastroenteropancreatic origin.
Toxicity of a combined therapy using the mTOR-inhibitor everolimus and PRRT with [Lu]Lu-DOTA-TATE in Lewis rats
Zellmer J, Yen HY, Kaiser L, Mille E, Gildehaus FJ, Böning G, Steiger K, Hacker M, Bartenstein P, Todica A, Haug AR and Ilhan H
Toxicity of a combined therapy using the mTOR-inhibitor everolimus and PRRT with [Lu]Lu-DOTA-TATE in Lewis rats
Zellmer J, Yen HY, Kaiser L, Mille E, Gildehaus FJ, Böning G, Steiger K, Hacker M, Bartenstein P, Todica A, Haug AR and Ilhan H
Peptide receptor radionuclide therapy (PRRT) with [Lu]Lu-DOTA,TYR-octreotate ([Lu]Lu-DOTA-TATE) and the mechanistic target of rapamycin (mTOR) inhibitor everolimus are both approved for the treatment of neuroendocrine tumours (NET). However, tumour progression is still frequent, and treatment strategies need further improvement. One possible approach could be to combine different therapy options. In this study, we investigated the toxicity of a combined treatment with everolimus and [Lu]Lu-DOTA-TATE in female Lewis rats.
-Cyclooctene-Functionalized PeptoBrushes with Improved Reaction Kinetics of the Tetrazine Ligation for Pretargeted Nuclear Imaging
Stéen EJL, Jørgensen JT, Johann K, Nørregaard K, Sohr B, Svatunek D, Birke A, Shalgunov V, Edem PE, Rossin R, Seidl C, Schmid F, Robillard MS, Kristensen JL, Mikula H, Barz M, Kjær A and Herth MM
-Cyclooctene-Functionalized PeptoBrushes with Improved Reaction Kinetics of the Tetrazine Ligation for Pretargeted Nuclear Imaging
Stéen EJL, Jørgensen JT, Johann K, Nørregaard K, Sohr B, Svatunek D, Birke A, Shalgunov V, Edem PE, Rossin R, Seidl C, Schmid F, Robillard MS, Kristensen JL, Mikula H, Barz M, Kjær A and Herth MM
Tumor targeting using agents with slow pharmacokinetics represents a major challenge in nuclear imaging and targeted radionuclide therapy as they most often result in low imaging contrast and high radiation dose to healthy tissue. To address this challenge, we developed a polymer-based targeting agent that can be used for pretargeted imaging and thus separates tumor accumulation from the imaging step in time. The developed targeting agent is based on polypeptide--polypeptoid polymers (PeptoBrushes) functionalized with -cyclooctene (TCO). The complementary In-labeled imaging agent is a 1,2,4,5-tetrazine derivative, which can react with aforementioned TCO-modified PeptoBrushes in a rapid bioorthogonal ligation. A high degree of TCO loading (up to 30%) was achieved, without altering the physicochemical properties of the polymeric nanoparticle. The highest degree of TCO loading resulted in significantly increased reaction rates (77-fold enhancement) compared to those with small molecule TCO moieties when using lipophilic tetrazines. Based on computer simulations, we hypothesize that this increase is a result of hydrophobic effects and significant rearrangements within the polymer framework, in which hydrophobic patches of TCO moieties are formed. These patches attract lipophilic tetrazines, leading to increased reaction rates in the bioorthogonal ligation. The most reactive system was evaluated as a targeting agent for pretargeted imaging in tumor-bearing mice. After the setup was optimized, sufficient tumor-to-background ratios were achieved as early as 2 h after administration of the tetrazine imaging agent, which further improved at 22 h, enabling clear visualization of CT-26 tumors. These findings show the potential of PeptoBrushes to be used as a pretargeting agent when an optimized dose of polymer is used.
EANM procedure guidelines for radionuclide therapy with Lu-labelled PSMA-ligands (Lu-PSMA-RLT)
Kratochwil C, Fendler WP, Eiber M, Baum R, Bozkurt MF, Czernin J, Delgado Bolton RC, Ezziddin S, Forrer F, Hicks RJ, Hope TA, Kabasakal L, Konijnenberg M, Kopka K, Lassmann M, Mottaghy FM, Oyen W, Rahbar K, Schöder H, Virgolini I, Wester HJ, Bodei L, Fanti S, Haberkorn U and Herrmann K
EANM procedure guidelines for radionuclide therapy with Lu-labelled PSMA-ligands (Lu-PSMA-RLT)
Kratochwil C, Fendler WP, Eiber M, Baum R, Bozkurt MF, Czernin J, Delgado Bolton RC, Ezziddin S, Forrer F, Hicks RJ, Hope TA, Kabasakal L, Konijnenberg M, Kopka K, Lassmann M, Mottaghy FM, Oyen W, Rahbar K, Schöder H, Virgolini I, Wester HJ, Bodei L, Fanti S, Haberkorn U and Herrmann K
Prostate-specific membrane antigen (PSMA) is expressed in most prostate cancers and can be identified by PSMA-ligand imaging, which has already become clinically accepted in several countries in- and outside Europe. PSMA-directed radioligand therapy (PSMA-RLT) with Lutetium-177 (Lu-PSMA) is currently undergoing clinical validation. Retrospective observational data have documented favourable safety and striking clinical responses. Recent results from a prospective clinical trial (phase II) have been published confirming high response rates, low toxicity and reduction of pain in metastatic castration-resistant prostate cancer (mCRPC) patients who had progressed after conventional treatments. Such patients typically survive for periods less than 1.5 years. This has led some facilities to adopt compassionate or unproven use of this therapy, even in the absence of validation within a randomised-controlled trial. As a result, a consistent body of evidence exists to support efficacy and safety data of this treatment. The purpose of this guideline is to assist nuclear medicine specialists to deliver PSMA-RLT as an "unproven intervention in clinical practice", in accordance with the best currently available knowledge.
Renal Cell Carcinoma: the Oncologist Asks, Can PSMA PET/CT Answer?
Pozzessere C, Bassanelli M, Ceribelli A, Rasul S, Li S, Prior JO and Cicone F
Renal Cell Carcinoma: the Oncologist Asks, Can PSMA PET/CT Answer?
Pozzessere C, Bassanelli M, Ceribelli A, Rasul S, Li S, Prior JO and Cicone F
To critically review the potential clinical applications of prostate-specific membrane antigen (PSMA) radioactive ligands in renal cell carcinoma (RCC).
European Association of Nuclear Medicine Practice Guideline/Society of Nuclear Medicine and Molecular Imaging Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma
Taïeb D, Hicks RJ, Hindié E, Guillet BA, Avram A, Ghedini P, Timmers HJ, Scott AT, Elojeimy S, Rubello D, Virgolini IJ, Fanti S, Balogova S, Pandit-Taskar N and Pacak K
European Association of Nuclear Medicine Practice Guideline/Society of Nuclear Medicine and Molecular Imaging Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma
Taïeb D, Hicks RJ, Hindié E, Guillet BA, Avram A, Ghedini P, Timmers HJ, Scott AT, Elojeimy S, Rubello D, Virgolini IJ, Fanti S, Balogova S, Pandit-Taskar N and Pacak K
Diverse radionuclide imaging techniques are available for the diagnosis, staging, and follow-up of phaeochromocytoma and paraganglioma (PPGL). Beyond their ability to detect and localise the disease, these imaging approaches variably characterise these tumours at the cellular and molecular levels and can guide therapy. Here we present updated guidelines jointly approved by the EANM and SNMMI for assisting nuclear medicine practitioners in not only the selection and performance of currently available single-photon emission computed tomography and positron emission tomography procedures, but also the interpretation and reporting of the results.
Ga-DOTATOC PET/CT in the localization of head and neck paraganglioma compared with F-DOPA PET/CT and I-MIBG SPECT/CT
Kroiss AS, Uprimny C, Shulkin BL, Gruber L, Frech A, Url C, Riechelmann H, Sprinzl GM, Thomé C, Treglia G, Kjaer A, Fraedrich G and Virgolini IJ
Ga-DOTATOC PET/CT in the localization of head and neck paraganglioma compared with F-DOPA PET/CT and I-MIBG SPECT/CT
Kroiss AS, Uprimny C, Shulkin BL, Gruber L, Frech A, Url C, Riechelmann H, Sprinzl GM, Thomé C, Treglia G, Kjaer A, Fraedrich G and Virgolini IJ
F-Fluoro-L-dihydroxyphenylalanine (F-DOPA) PET offers high sensitivity and specificity in the imaging of non-malignant head and neck paraganglioma (HNPGL) but lower sensitivity in metastatic disease of these neuroendocrine tumours (NET). In contrast to the radiotracer F-DOPA, both I-meta-iodo-benzylguanidine (I-MIBG) and Ga-DOTA-Tyr3-octreotide (Ga-DOTA-TOC) offer valuable clinical information on norepinephrine and somatostatin (SST) receptor status for planning I-MIBG and radionuclide peptide therapy (PRRT), respectively. Therefore, we compared Ga-DOTA-TOC and F-DOPA PET/CT with I-MIBG planar and SPECT/CT imaging, for the detection of HNPGL. Combined cross-sectional imaging was the reference standard.