119 results on '"Calogero, D'Alessandria"'
Search Results
2. Matched-pair analysis of mCRPC patients receiving 177Lu-labeled PSMA-targeted radioligand therapy in a 4-week versus 6-week treatment interval
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Amir Karimzadeh, Charlotte-Sophie Hecker, Matthias M. Heck, Robert Tauber, Calogero D’Alessandria, Wolfgang A. Weber, Matthias Eiber, and Isabel Rauscher
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Prostate-specific membrane antigen (PSMA) ,Radioligand therapy (RLT) ,Metastatic castration-resistant prostate cancer (mCRPC) ,4-week treatment interval ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
Abstract Background The optimal regimen for 177Lu-labeled prostate-specific membrane antigen-targeted radioligand therapy, including treatment intervals, remains under study, with evidence suggesting shorter intervals could benefit patients with high disease volume and rapid progression. This retrospective analysis evaluated treatment toxicity, PSA response, PSA-progression-free survival (PSA-PFS), and overall survival (OS) in matched cohorts of mCRPC patients receiving 177Lu-PSMA-RLT at 4-week versus 6-week intervals. Results A PSA response (PSA decline ≥ 50%) was achieved in 47.8% and 21.7% of patients in the 4-week and 6-week treatment interval groups, respectively (p = 0.12). There was a trend towards longer PSA-PFS in the 4-week group compared to the 6-week group (median PSA-PFS, 26.0 weeks vs. 18.0 weeks; HR 0.6; p = 0.2). Although not statistically significant, there was a trend towards shorter OS in the 4-week group compared to the 6-week group (median OS, 15.1 months vs. 18.4 months; HR 1.3; p = 0.5). The 4-week group had a significantly greater decrease in leucocyte and platelet counts compared to the 6-week group (38.5% vs. 18.2% and 26.7% vs. 10.7%; p = 0.047 and p = 0.02). Severe adverse events were modest in both groups. Conclusions Intensifying treatment intervals from 6 weeks to 4 weeks showed some improvements in PSA response and PSA-PFS for mCRPC patients, but did not significantly affect OS. Additionally, bone marrow reserve was significantly reduced with the intensified regimen. Therefore, the overall benefit remains uncertain, and further prospective studies are needed to compare 4-week and 6-week intervals regarding toxicity, treatment response, and outcome.
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- 2024
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3. Galectin-3 and cancer immunotherapy: a glycobiological rationale to overcome tumor immune escape
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Giorgia Scafetta, Calogero D’Alessandria, and Armando Bartolazzi
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Immunotherapy, Checkpoint inhibitors ,Galectin-3 ,Tumor microenvironment ,Predictive markers of immune-response ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Immunotherapy with checkpoint inhibitors (ICIs) has radically changed the landscape of therapeutic opportunities in oncology, but much still needs to be understood from a mechanistic point of view. There is space for further improving tumors’ response to ICIs, as supported by a strong biological rationale. For this achievement a detailed analysis of tumor cell phenotype with functional dissection of the molecular interactions occurring in the TME is required. Galectin-3 is a pleiotropic tumor relevant molecule, which deserves particular attention in immuno-oncology. Due to its ability to finely modulate immune response in vivo, Galectin-3 is a potential target molecule to be considered for overcoming tumor immune escape.
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- 2024
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4. Preclinical comparison of [177Lu]Lu-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.2 for endoradiotherapy of prostate cancer: biodistribution and dosimetry studies
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Alexander Wurzer, Francesco De Rose, Sebastian Fischer, Markus Schwaiger, Wolfgang Weber, Stephan Nekolla, Hans-Jürgen Wester, Matthias Eiber, and Calogero D’Alessandria
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Prostate cancer ,Radioligand therapy ,Radiohybrid ,rhPSMA ,PSMA ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract Background Radiohybrid PSMA-targeted ligands (rhPSMA) have been introduced as a novel platform for theranostic applications. Among a variety of rhPSMA-ligands developed for radioligand therapy, two stereoisomers [177Lu]Lu-rhPSMA-10.1 and -10.2 have been synthesized and initially characterized in preclinical experiments with the aim to provide an optimized binding profile to human serum albumin, a reduction of charge, and thus accelerated kidney excretion, and unaffected or even improved tumor uptake. As both isomers showed similar in vitro characteristics and tumor uptake at 24 h post injection in tumor bearing mice and in order to identify the isomer with the most favorable pharmacokinetics for radioligand therapy, we carried out in-depth biodistribution and dosimetry studies in tumor-bearing and healthy mice. Results rhPSMA-10.1 and -10.2 were radiolabeled with lutetium-177 according to the established procedures of other DOTA-based PSMA ligands and displayed a high and comparable stability in all buffers and human serum (> 97%, 24 h). Biodistribution studies revealed fast clearance from the blood pool (0.3–0.6%ID/g at 1 h) and other background tissues within 48 h. Distinctive differences were found in the kidneys, where [177Lu]Lu-rhPSMA-10.1 displayed lower initial uptake and faster excretion kinetics compared to [177Lu]Lu-rhPSMA-10.2 expressed by a 1.5-fold and ninefold lower uptake value at 1 h and 24 h in healthy animals, respectively. Tumor uptake was comparable and in the range of 8.6–11.6%ID/g for both isomers over 24 h and was maintained up to 168 h at a level of 2.2 ± 0.8 and 4.1 ± 1.4%ID/g for [177Lu]Lu-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.2, respectively. Conclusion Our preclinical data on biodistribution and dosimetry indicate a more favorable profile of [177Lu]Lu-rhPSMA-10.1 compared to [177Lu]Lu-rhPSMA-10.2 for PSMA-targeted radioligand therapy. [177Lu]Lu-rhPSMA-10.1 shows fast kidney clearance kinetics resulting in excellent tumor-to-organ ratios over a therapy relevant time course. Meanwhile, [177Lu]Lu-rhPSMA-10.1 is currently being investigated in clinical phase I/II studies in patients with mCRPC (NCT05413850), in patients with high-risk localized PC (NCT06066437, Nautilus Trial) and after external beam radiotherapy (NCT06105918).
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- 2024
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5. In silico study on radiobiological efficacy of Ac-225 and Lu-177 for PSMA-guided radiotherapy.
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Gabriele Birindelli, Milos Drobnjakovic, Volker Morath, Katja Steiger, Calogero D'Alessandria, Eleni Gourni, Ali Afshar-Oromieh, Wolfgang Weber 0005, Axel Rominger, Matthias Eiber, and Kuangyu Shi
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- 2021
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6. Preclinical biodistribution and dosimetry and human biodistribution comparing 18F-rhPSMA-7 and single isomer 18F-rhPSMA-7.3
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Karina Knorr, So Won Oh, Markus Krönke, Alexander Wurzer, Calogero D’Alessandria, Michael Herz, Wolfgang Weber, Hans-Jürgen Wester, Matthias Eiber, Nahid Yusufi, and Stephan Nekolla
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18F ,Biodistribution ,Dosimetry ,PET/CT ,PSMA ,rhPSMA ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
Abstract Background Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands such as 18F-rhPSMA-7 are a new class of theranostic agents in clinical development for prostate cancer. We compared preclinical dosimetry and human biodistribution of 18F-rhPSMA-7 with that of single diastereoisomer form, 18F-rhPSMA-7.3. Methods Preclinical dosimetry was performed with SCID-mice sacrificed at multiple timepoints (10–300 min) post-injection of 25.6 ± 3.6 MBq 18F-rhPSMA-7 or 28.5 ± 4.8 MBq 18F-rhPSMA-7.3 (n = 3–6 mice per timepoint). Heart, lung, liver, spleen, pancreas, fat, stomach, small intestine, large intestine, kidney, muscle, bone, bladder, testicles, tail, and brain tissue were harvested, and urine and blood samples collected. Percentage of injected dose per gram was calculated. Absorbed doses were estimated with OLINDA/EXM 1.0. 18F-rhPSMA-7 (n = 47) and 18F-rhPSMA-7.3 (n = 33) PET/CT exams were used to estimate human biodistribution. Mean (range) injected activities were 324 (236–424) MBq versus 345 (235–420) MBq, and acquisition times were 84 (42–166) versus 76 (59–122) minutes for 18F-rhPSMA-7 versus 18F-rhPSMA-7.3, respectively. SUVmean was determined for background (gluteal muscle), normal organs (salivary glands, blood pool, lung, liver, spleen, pancreas, duodenum, kidney, bladder, bone) and up to three representative tumour lesions. Qualitative analyses assessed image quality, non-specific blood pool activity, and background uptake in bone/marrow using 3/4-point scales. Results Preclinical dosimetry revealed that at 3.5 h and 1 h bladder voiding intervals, the extrapolated total effective doses were 26.6 and 12.2 µSv/MBq for 18F-rhPSMA-7 and 21.7 and 12.8 µSv/MBq for 18F-rhPSMA-7.3 respectively. Human biodistribution of both agents was typical of other PSMA-ligands and broadly similar to each other; SUVmean were 16.9 versus 16.2 (parotid gland), 19.6 versus 19.9 (submandibular gland), 2.0 versus 1.9 (blood pool, p
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- 2022
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7. Promise and challenges of clinical non-invasive T-cell tracking in the era of cancer immunotherapy
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Dario Gosmann, Lisa Russelli, Wolfgang A. Weber, Markus Schwaiger, Angela M. Krackhardt, and Calogero D’Alessandria
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Cancer immunotherapy ,Tumor-reactive T-cells ,Immuno-imaging ,Positron emission tomography ,Response evaluation ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
Abstract In the last decades, our understanding of the role of the immune system in cancer has significantly improved and led to the discovery of new immunotherapeutic targets and tools, which boosted the advances in cancer immunotherapy to fight a growing number of malignancies. Approved immunotherapeutic approaches are currently mainly based on immune checkpoint inhibitors, antibody-derived targeted therapies, or cell-based immunotherapies. In essence, these therapies induce or enhance the infiltration and function of tumor-reactive T cells within the tumors, ideally resulting in complete tumor eradication. While the clinical application of immunotherapies has shown great promise, these therapies are often accompanied either by a variety of side effects as well as partial or complete unresponsiveness of a number of patients. Since different stages of disease progression elicit different local and systemic immune responses, the ability to longitudinally interrogate the migration and expansion of immune cells, especially T cells, throughout the whole body might greatly facilitate disease characterization and understanding. Furthermore, it can serve as a tool to guide development as well as selection of appropriate treatment regiments. This review provides an overview about a variety of immune-imaging tools available to characterize and study T-cell responses induced by anti-cancer immunotherapy. Moreover, challenges are discussed that must be taken into account and overcome to use immune-imaging tools as predictive and surrogate markers to enhance assessment and successful application of immunotherapies.
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- 2022
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8. Effective rational humanization of a PASylated anti-galectin-3 Fab for the sensitive PET imaging of thyroid cancer in vivo
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Emanuel Peplau, Francesco De Rose, Andreas Eichinger, Sybille Reder, Markus Mittelhäuser, Giorgia Scafetta, Markus Schwaiger, Wolfgang A. Weber, Armando Bartolazzi, Calogero D’Alessandria, and Arne Skerra
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Medicine ,Science - Abstract
Abstract The lack of a non-invasive test for malignant thyroid nodules makes the diagnosis of thyroid cancer (TC) challenging. Human galectin-3 (hGal3) has emerged as a promising target for medical TC imaging and diagnosis because of its exclusive overexpression in malignant thyroid tissues. We previously developed a human-chimeric αhGal3 Fab fragment derived from the rat monoclonal antibody (mAb) M3/38 with optimized clearance characteristics using PASylation technology. Here, we describe the elucidation of the hGal3 epitope recognized by mAb M3/38, X-ray crystallographic analysis of its complex with the chimeric Fab and, based on the three-dimensional structure, the rational humanization of the Fab by CDR grafting. Four CDR-grafted versions were designed using structurally most closely related fully human immunoglobulin VH/VL regions of which one—employing the acceptor framework regions of the HIV-1 neutralizing human antibody m66—showed the highest antigen affinity. By introducing two additional back-mutations to the rodent donor sequence, an affinity toward hGal3 indistinguishable from the chimeric Fab was achieved (KD = 0.34 ± 0.02 nM in SPR). The PASylated humanized Fab was site-specifically labelled with the fluorescent dye Cy7 and applied for the immuno-histochemical staining of human tissue sections representative for different TCs. The same protein was conjugated with the metal chelator Dfo, followed by radiolabelling with 89Zr(IV). The resulting protein tracer allowed the highly sensitive and specific PET/CT imaging of orthotopic tumors in mice, which was confirmed by quantitative analysis of radiotracer accumulation. Thus, the PASylated humanized αhGal3 Fab offers clinical potential for the diagnostic imaging of TC.
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- 2021
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9. Non-conventional and Investigational PET Radiotracers for Breast Cancer: A Systematic Review
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Michele Balma, Virginia Liberini, Manuela Racca, Riccardo Laudicella, Matteo Bauckneht, Ambra Buschiazzo, Daniele Giovanni Nicolotti, Simona Peano, Andrea Bianchi, Giovanni Albano, Natale Quartuccio, Ronan Abgral, Silvia Daniela Morbelli, Calogero D'Alessandria, Enzo Terreno, Martin William Huellner, Alberto Papaleo, and Désirée Deandreis
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PET ,breast cancer ,radiotracers ,molecular imaging ,FES ,FLT ,Medicine (General) ,R5-920 - Abstract
Breast cancer is one of the most common malignancies in women, with high morbidity and mortality rates. In breast cancer, the use of novel radiopharmaceuticals in nuclear medicine can improve the accuracy of diagnosis and staging, refine surveillance strategies and accuracy in choosing personalized treatment approaches, including radioligand therapy. Nuclear medicine thus shows great promise for improving the quality of life of breast cancer patients by allowing non-invasive assessment of the diverse and complex biological processes underlying the development of breast cancer and its evolution under therapy. This review aims to describe molecular probes currently in clinical use as well as those under investigation holding great promise for personalized medicine and precision oncology in breast cancer.
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- 2022
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10. Hyperkalemia in patients treated with endoradiotherapy combined with amino acid infusion is associated with severe metabolic acidosis
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Christian H. Pfob, Matthias Eiber, Peter Luppa, Florian Maurer, Tobias Maurer, Robert Tauber, Calogero D’Alessandria, Benedikt Feuerecker, Klemens Scheidhauer, Armin Ott, Uwe Heemann, Markus Schwaiger, and Christoph Schmaderer
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Hyperkalemia ,Radiotherapy ,PRRT ,RLT ,Amino acid ,Prostate cancer ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
Abstract Background Amino acid co-infusion for renal protection in endoradiotherapy (ERT) applied as prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) or peptide receptor radionuclide therapy (PRRT) has been shown to cause severe hyperkalemia. The pathophysiology behind the rapid development of hyperkalemia is not well understood. We hypothesized that the hyperkalemia should be associated with metabolic acidosis. Results Twenty-two patients underwent ERT. Prior to the first cycle, excretory kidney function was assessed by mercapto-acetyltriglycine (MAG-3) renal scintigraphy, serum biochemistry, and calculated glomerular filtration rate (eGFR). All patients received co-infusion of the cationic amino acids L-arginine and L-lysine for nephroprotection. Clinical symptoms, electrolytes, and acid-base status were evaluated at baseline and after 4 h. No patient developed any clinically relevant side effects. At baseline, acid base status and electrolytes were normal in all patients. Excretory kidney function was normal or only mildly impaired in all except two patients with stage 3 renal insufficiency. All patients developed hyperkalemia. Base excess and HCO3 − were significantly lower after 4 h. In parallel, mean pH dropped from 7.36 to 7.29. There was a weak association between calculated (r = − 0.21) as well as MAG-3-derived GFR (r = − 0.32) and the rise in potassium after 4 h. Conclusion Amino acid co-infusion during ERT leads to severe metabolic acidosis which induces hyperkalemia by potassium hydrogen exchange. This novel finding implies that commercially available bicarbonate solutions might be an easy therapeutic option to correct metabolic acidosis rapidly.
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- 2018
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11. A Semi Rigid Novel Hydroxamate AMPED-Based Ligand for 89Zr PET Imaging
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Lisa Russelli, Francesco De Rose, Loredana Leone, Sybille Reder, Markus Schwaiger, Calogero D’Alessandria, and Lorenzo Tei
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zirconium-89 ,polydentate chelators ,hydroxamates ,PET-imaging ,labeling ,Organic chemistry ,QD241-441 - Abstract
In this work, we designed, developed, characterized, and investigated a new chelator and its bifunctional derivative for 89Zr labeling and PET-imaging. In a preliminary study, we synthesized two hexadentate chelators named AAZTHAS and AAZTHAG, based on the seven-membered heterocycle AMPED (6-amino-6-methylperhydro-1,4-diazepine) with the aim to increase the rigidity of the 89Zr complex by using N-methyl-N-(hydroxy)succinamide or N-methyl-N-(hydroxy)glutaramide pendant arms attached to the cyclic structure. N-methylhydroxamate groups are the donor groups chosen to efficiently coordinate 89Zr. After in vitro stability tests, we selected the chelator with longer arms, AAZTHAG, as the best complexing agent for 89Zr presenting a stability of 86.4 ± 5.5% in human serum (HS) for at least 72 h. Small animal PET/CT static scans acquired at different time points (up to 24 h) and ex vivo organ distribution studies were then carried out in healthy nude mice (n = 3) to investigate the stability and biodistribution in vivo of this new 89Zr-based complex. High stability in vivo, with low accumulation of free 89Zr in bones and kidneys, was measured. Furthermore, an activated ester functionalized version of AAZTHAG was synthesized to allow the conjugation with biomolecules such as antibodies. The bifunctional chelator was then conjugated to the human anti-HER2 monoclonal antibody Trastuzumab (Tz) as a proof of principle test of conjugation to biologically active molecules. The final 89Zr labeled compound was characterized via radio-HPLC and SDS-PAGE followed by autoradiography, and its stability in different solutions was assessed for at least 4 days.
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- 2021
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12. 177Lu-PSMA-I&T for Treatment of Metastatic Castration-Resistant Prostate Cancer: Prognostic Value of Scintigraphic and Clinical Biomarkers
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Amir Karimzadeh, Matthias Heck, Robert Tauber, Karina Knorr, Bernhard Haller, Calogero D’Alessandria, Wolfgang A. Weber, Matthias Eiber, and Isabel Rauscher
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Radiology, Nuclear Medicine and imaging - Published
- 2022
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13. Stand der Technik in der Radiopharmazie
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Alexander Wurzer, Stephan G. Nekolla, and Calogero D’Alessandria
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ZusammenfassungDie wachsende Zahl potenzieller Radioisotope und die steigende Nachfrage nach Radiopharmazeutika (RP) für Bildgebung- und Therapiezwecke haben dazu geführt, dass ihre biomedizinische Anwendung im modernen Gesundheitswesen immer mehr an Bedeutung gewinnt. Die nuklearmedizinische Technologie wird heute als ein wesentliches Instrument für Diagnose, Palliation, Therapie und theranostische Anwendungen angesehen. Die damit verbundene Produktion unter Einhaltung der guten Herstellungspraxis (GMP) und Fragen der Strahlensicherheit müssen in Form von angemessenen Regulierungsmaßnahmen hervorgehoben werden, um ihren sicheren und wirksamen Einsatz zu gewährleisten. Die RP ziehen aufgrund ihrer pharmazeutischen und radioaktiven Bestandteile die Aufmerksamkeit sowohl der pharmazeutischen als auch der gesundheitstechnischer Aufsichtsbehörden auf sich. Diese Arbeit gibt einen kurzen Überblick über die RP und die jüngsten Studien zur diagnostischen, therapeutischen und theranostischen Anwendung. Die vorliegende Arbeit erörtert die Bedeutung von RP im aktuellen Gesundheitsbereich, ihre jüngsten Anwendungen und bemüht sich, die Bedeutung eines harmonisierten Regelwerkes hervorzuheben.
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- 2022
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14. Synthesis and Preclinical Evaluation of 177Lu-Labeled Radiohybrid PSMA Ligands for Endoradiotherapy of Prostate Cancer
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Alexander Wurzer, Jan-Philip Kunert, Sebastian Fischer, Veronika Felber, Roswitha Beck, Francesco de Rose, Calogero D’Alessandria, Wolfgang Weber, and Hans-Jürgen Wester
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Radiology, Nuclear Medicine and imaging - Published
- 2022
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15. Table S2 from Noninvasive In Vivo Imaging and Biologic Characterization of Thyroid Tumors by ImmunoPET Targeting of Galectin-3
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Armando Bartolazzi, Markus Schwaiger, Birgit Blechert, Sybille Reder, Kristel Bejo, Sten Braesch-Andersen, and Calogero D'Alessandria
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Biodistribution analysis of 89Zr-labelled anti-Gal3 mAb in three different animal models.
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- 2023
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16. Supplementary Figure S3A-D from Preclinical Evaluation of the Hsp70 Peptide Tracer TPP-PEG24-DFO[89Zr] for Tumor-Specific PET/CT Imaging
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Gabriele Multhoff, Calogero D'Alessandria, Markus Schwaiger, Roland Rad, Rupert Öllinger, Maxim Shevtsov, Wolfgang Sievert, Jonathan Martinelli, Sybille Reder, Francesco De Rose, Lorenzo Tei, and Stefan Stangl
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Radio-TLC Analysis and stability testing of TPP-PEG24-DFO[89Zr] and cmHsp70.1-DFO[89]
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- 2023
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17. Data from Noninvasive In Vivo Imaging and Biologic Characterization of Thyroid Tumors by ImmunoPET Targeting of Galectin-3
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Armando Bartolazzi, Markus Schwaiger, Birgit Blechert, Sybille Reder, Kristel Bejo, Sten Braesch-Andersen, and Calogero D'Alessandria
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The high prevalence of thyroid nodules in the adult population and the relatively low incidence of thyroid cancer make the preoperative identification of malignant lesions challenging. The β-galactoside–binding protein galectin-3 is widely expressed in well-differentiated thyroid carcinomas, but not in normal thyrocytes and benign thyroid nodules. This molecule offers a candidate biomarker to improve thyroid cancer diagnosis. Here we report the development of an immunoPET approach for noninvasive imaging of thyroid cancer. The method employs a 89Zr-labeled mAb to galectin-3, which shows high specificity and binding affinity in vitro. Reliable and specific immunoPET imaging was obtained of thyroid cancer in vivo in murine xenograft models of human thyroid cancer. Our findings provide a method to improve the clinical management of patients with thyroid nodules while reducing unnecessary surgery and social costs. Cancer Res; 76(12); 3583–92. ©2016 AACR.
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- 2023
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18. Supplementary Figure S7A-B from Preclinical Evaluation of the Hsp70 Peptide Tracer TPP-PEG24-DFO[89Zr] for Tumor-Specific PET/CT Imaging
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Gabriele Multhoff, Calogero D'Alessandria, Markus Schwaiger, Roland Rad, Rupert Öllinger, Maxim Shevtsov, Wolfgang Sievert, Jonathan Martinelli, Sybille Reder, Francesco De Rose, Lorenzo Tei, and Stefan Stangl
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In vivo stability of TPP-PEG24-DFO[89Zr] in blood, kidney, liver, 4T1 and CT26 tumors
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- 2023
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19. Supplementary Materials and Figure legends S1-S7 from Preclinical Evaluation of the Hsp70 Peptide Tracer TPP-PEG24-DFO[89Zr] for Tumor-Specific PET/CT Imaging
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Gabriele Multhoff, Calogero D'Alessandria, Markus Schwaiger, Roland Rad, Rupert Öllinger, Maxim Shevtsov, Wolfgang Sievert, Jonathan Martinelli, Sybille Reder, Francesco De Rose, Lorenzo Tei, and Stefan Stangl
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Synthesis, characterization and in vitro and in vivo stability testing of TPP-PEG24-DFO[89Zr] and histological analysis of a benign fibroblast hyperplasia
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- 2023
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20. Data from Preclinical Evaluation of the Hsp70 Peptide Tracer TPP-PEG24-DFO[89Zr] for Tumor-Specific PET/CT Imaging
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Gabriele Multhoff, Calogero D'Alessandria, Markus Schwaiger, Roland Rad, Rupert Öllinger, Maxim Shevtsov, Wolfgang Sievert, Jonathan Martinelli, Sybille Reder, Francesco De Rose, Lorenzo Tei, and Stefan Stangl
- Abstract
High precision in vivo PET/CT imaging of solid tumors improves diagnostic credibility and clinical outcome of patients. An epitope of the oligomerization domain of Hsp70 is exclusively exposed on the membrane of a large variety of tumor types, but not on normal cells, and thus provides a universal tumor-specific target. Here we developed a novel PET tracer TPP-PEG24-DFO[89Zr] based on the tumor cell–penetrating peptide probe TPP, which specifically recognizes membrane Hsp70 (mHsp70) on tumor cells. The implemented PEG24 moiety supported tracer stability and improved biodistribution characteristics in vivo. The Kd of the tracer ranged in the low nanomolar range (18.9 ± 11.3 nmol/L). Fluorescein isothiocyanate (FITC)-labeled derivatives TPP-[FITC] and TPP-PEG24-[FITC] revealed comparable and specific binding to mHsp70-positive 4T1, 4T1+, a derivative of the 4T1 cell line sorted for high Hsp70 expression, and CT26 tumor cells, but not to mHsp70-negative normal fibroblasts. The rapid internalization kinetics of mHsp70 into the cytosol and the favorable biodistribution of the peptide-based tracer TPP-PEG24-DFO[89Zr] in vivo enabled a tumor-specific accumulation with a high tumor-to-background contrast and renal body clearance. The tumor-specific enrichment of the tracer in 4T1+ (6.2 ± 1.1%ID/g), 4T1 (4.3 ± 0.7%ID/g), and CT26 (2.6 ± 0.6%ID/g) mouse tumors with very high, high, and intermediate mHsp70 densities, respectively, reflected mHsp70 expression profiles of the different tumor types, whereas benign mHsp70-negative fibroblastic hyperplasia showed no tracer accumulation (0.2 ± 0.03%ID/g). The ability of our chemically optimized peptide-based tracer TPP-PEG24-DFO[89Zr] to detect mHsp70 in vivo suggests its broad applicability in targeting and imaging with high specificity for any tumor type that exhibits surface expression of Hsp70.Significance: A novel peptide-based PET tracer against the oligomerization domain of Hsp70 has potential for universal tumor-specific imaging in vivo across many tumor type. Cancer Res; 78(21); 6268–81. ©2018 AACR.
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- 2023
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21. Supplementary Figure S4A-C from Preclinical Evaluation of the Hsp70 Peptide Tracer TPP-PEG24-DFO[89Zr] for Tumor-Specific PET/CT Imaging
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Gabriele Multhoff, Calogero D'Alessandria, Markus Schwaiger, Roland Rad, Rupert Öllinger, Maxim Shevtsov, Wolfgang Sievert, Jonathan Martinelli, Sybille Reder, Francesco De Rose, Lorenzo Tei, and Stefan Stangl
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Histological section of benign fibroblat hyperplasia (A), H&E (B), and Hsp70 (C) immunohistochemical staining
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- 2023
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22. Supplemental Material and Methods from Noninvasive In Vivo Imaging and Biologic Characterization of Thyroid Tumors by ImmunoPET Targeting of Galectin-3
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Armando Bartolazzi, Markus Schwaiger, Birgit Blechert, Sybille Reder, Kristel Bejo, Sten Braesch-Andersen, and Calogero D'Alessandria
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Description of additional methods and procedures used in the study.
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- 2023
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23. Supplementary Figure 5A-E from Preclinical Evaluation of the Hsp70 Peptide Tracer TPP-PEG24-DFO[89Zr] for Tumor-Specific PET/CT Imaging
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Gabriele Multhoff, Calogero D'Alessandria, Markus Schwaiger, Roland Rad, Rupert Öllinger, Maxim Shevtsov, Wolfgang Sievert, Jonathan Martinelli, Sybille Reder, Francesco De Rose, Lorenzo Tei, and Stefan Stangl
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In vitro characterization of TPP-PEG24-DFO[89Zr]. KD analysis (A), IC50 (B), internalization kinetics (C), short-term (D) and long-term (E) time-activity analysis
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- 2023
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24. Figure S2 from Noninvasive In Vivo Imaging and Biologic Characterization of Thyroid Tumors by ImmunoPET Targeting of Galectin-3
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Armando Bartolazzi, Markus Schwaiger, Birgit Blechert, Sybille Reder, Kristel Bejo, Sten Braesch-Andersen, and Calogero D'Alessandria
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Immunohistochemical analysis of galectin-3 expression in normal tissues ex vivo.
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- 2023
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25. Supplemental Figure Legends from Noninvasive In Vivo Imaging and Biologic Characterization of Thyroid Tumors by ImmunoPET Targeting of Galectin-3
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Armando Bartolazzi, Markus Schwaiger, Birgit Blechert, Sybille Reder, Kristel Bejo, Sten Braesch-Andersen, and Calogero D'Alessandria
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Legends for Supplementary Figures S1-S2.
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- 2023
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26. Supplementary Figure S2A-F from Preclinical Evaluation of the Hsp70 Peptide Tracer TPP-PEG24-DFO[89Zr] for Tumor-Specific PET/CT Imaging
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Gabriele Multhoff, Calogero D'Alessandria, Markus Schwaiger, Roland Rad, Rupert Öllinger, Maxim Shevtsov, Wolfgang Sievert, Jonathan Martinelli, Sybille Reder, Francesco De Rose, Lorenzo Tei, and Stefan Stangl
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LC-MS trace and ESI-MS spectrum of TPP-DFO, Mal-PEG24-DFO, TPP-PEG24-DFO, TPP-PEG24-DFO-natZr, Mal-PEG24-FITC, and TPP-PEG24-FITC
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- 2023
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27. Supplementary Material and Figure Legends from Immuno-PET Imaging of Engineered Human T Cells in Tumors
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Angela M. Krackhardt, Calogero D'Alessandria, Markus Schwaiger, Mona Mustafa, Sibylle Ziegler, Christian Peschel, Michaela Aichler, Iina Laitinen, Stefan Audehm, Melanie Straub, Katja Steiger, Henrique Bianchi, Richard Klar, Ricarda Wagner, Nahid Yusufi, and Sabine Mall
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Supplementary Material and Figure Legends
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- 2023
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28. Data from Immuno-PET Imaging of Engineered Human T Cells in Tumors
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Angela M. Krackhardt, Calogero D'Alessandria, Markus Schwaiger, Mona Mustafa, Sibylle Ziegler, Christian Peschel, Michaela Aichler, Iina Laitinen, Stefan Audehm, Melanie Straub, Katja Steiger, Henrique Bianchi, Richard Klar, Ricarda Wagner, Nahid Yusufi, and Sabine Mall
- Abstract
Sensitive in vivo imaging technologies applicable to the clinical setting are still lacking for adoptive T-cell–based immunotherapies, an important gap to fill if mechanisms of tumor rejection or escape are to be understood. Here, we propose a highly sensitive imaging technology to track human TCR-transgenic T cells in vivo by directly targeting the murinized constant TCR beta domain (TCRmu) with a zirconium-89 (89Zr)-labeled anti–TCRmu-F(ab')2 fragment. Binding of the labeled or unlabeled F(ab')2 fragment did not impair functionality of transgenic T cells in vitro and in vivo. Using a murine xenograft model of human myeloid sarcoma, we monitored by Immuno-PET imaging human central memory T cells (TCM), which were transgenic for a myeloid peroxidase (MPO)–specific TCR. Diverse T-cell distribution patterns were detected by PET/CT imaging, depending on the tumor size and rejection phase. Results were confirmed by IHC and semiquantitative evaluation of T-cell infiltration within the tumor corresponding to the PET/CT images. Overall, these findings offer a preclinical proof of concept for an imaging approach that is readily tractable for clinical translation. Cancer Res; 76(14); 4113–23. ©2016 AACR.
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- 2023
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29. Supplementary Figure S2 from Immuno-PET Imaging of Engineered Human T Cells in Tumors
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Angela M. Krackhardt, Calogero D'Alessandria, Markus Schwaiger, Mona Mustafa, Sibylle Ziegler, Christian Peschel, Michaela Aichler, Iina Laitinen, Stefan Audehm, Melanie Straub, Katja Steiger, Henrique Bianchi, Richard Klar, Ricarda Wagner, Nahid Yusufi, and Sabine Mall
- Abstract
Investigation of different imaging time points to track TCR-transduced TCM after injection of 89Zr-aTCRmu-F(ab')2
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- 2023
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30. The prognostic role of
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Lukas, Lunger, Maythinee, Chantadisai, Amir, Karimzadeh, Isabel, Rauscher, Calogero, D'Alessandria, Benedikt, Feuerecker, Thomas, Langbein, Robert, Tauber, Stefan, Schiele, Wolfgang Andreas, Weber, and Matthias, Eiber
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To assess the prognostic utility of conventional biochemical and imaging response criteria and
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- 2022
31. Activity and Adverse Events of Actinium-225-PSMA-617 in Advanced Metastatic Castration-resistant Prostate Cancer After Failure of Lutetium-177-PSMA
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Matthias Heck, Alfred Morgenstern, Anja Pickhard, Calogero D'Alessandria, Matthias Eiber, Andrei Gafita, Jürgen E. Gschwend, Karina Knorr, Wolfgang A. Weber, Benedikt Feuerecker, Ali Beheshti, Christof Seidl, Robert Tauber, Clemens Kratochwil, Margitta Retz, and Frank Bruchertseifer
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Actinium ,Male ,Oncology ,medicine.medical_specialty ,Side effect ,Anemia ,Urology ,medicine.medical_treatment ,030232 urology & nephrology ,Lutetium ,urologic and male genital diseases ,Xerostomia ,Heterocyclic Compounds, 1-Ring ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Humans ,Medicine ,Enzalutamide ,Neoplasm Metastasis ,Adverse effect ,Retrospective Studies ,Radioisotopes ,Chemotherapy ,Taxane ,business.industry ,Dipeptides ,Prostate-Specific Antigen ,medicine.disease ,Prostatic Neoplasms, Castration-Resistant ,Treatment Outcome ,chemistry ,030220 oncology & carcinogenesis ,Toxicity ,Radiopharmaceuticals ,business - Abstract
Background Beta-emitting Lu-177-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a new option for metastatic castration-resistant prostate cancer (mCRPC), but its antitumor effect can decrease over time. Objective To report the safety and activity of alpha-emitting Ac-225-PSMA-617 RLT in mCRPC that has progressed after Lu-177-PSMA. Design, setting, and participants Twenty-six patients were treated under a compassionate use protocol. The eligibility criteria included previous treatment with abiraterone or enzalutamide, previous taxane-based chemotherapy, progression after Lu-177-PSMA, and positive PSMA-ligand uptake. The median number of previous mCRPC regimens was 6. Ac-225-PSMA-617 was given every 8 wk until progression/intolerable side effects. Outcome measurements and statistical analysis Prostate-specific antigen (PSA) decline, PSA progression-free survival (PSA-PFS), clinical progression-free survival (cPFS), overall survival (OS), and toxicity were measured. Results and limitations Sixty-one cycles of Ac-225-PSMA-617 (median number of cycles 2; median activity 9 MBq) were administered. A PSA decline of ≥50% was achieved in 17/26 patients. The median PSA-PFS, cPFS, and OS periods were 3.5 (95% confidence interval [CI] 1.8–11.2), 4.1 (95% CI 3–14.8), and 7.7 (95% CI 4.5–12.1) mo, respectively. Liver metastases were associated with shorter PSA-PFS (median 1.9 vs 4.0 mo; p = 0.02), cPFS (median 1.8 vs 5.2 mo; p = 0.001), and OS (median 4.3 vs 10.4 mo; p = 0.01). Hematological grade 3/4 toxicities were anemia (35%), leucopenia (27%), and thrombocytopenia (19%). All patients experienced grade 1/2 xerostomia. Two and six patients stopped due to hematological toxicity and xerostomia, respectively. A limitation is the retrospective design. Conclusions Ac-225-PSMA-617 showed measurable antitumor effect after Lu-177-PSMA failure in late-stage mCRPC. Grade 3/4 hematological side effects were observed in up to one-third of patients, and xerostomia led to treatment halt in a relevant number of patients. Patient summary Ac-225-labeled prostate-specific membrane antigen (PSMA)-617 therapy showed substantial antitumor effect in late metastatic castration-resistant prostate cancer after Lu-177-PSMA failure. However, dry mouth is a common side effect that caused about a quarter of patients to stop therapy.
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- 2021
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32. Comparative Preclinical Biodistribution, Dosimetry, and Endoradiotherapy in Metastatic Castration-Resistant Prostate Cancer Using 19F/177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T
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Stephan G. Nekolla, Calogero D'Alessandria, Alexander Wurzer, Wolfgang A. Weber, Nahid Yusufi, Michael Herz, Benedikt Feuerecker, Matthias Eiber, and Hans-Juergen Wester
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Biodistribution ,Severe combined immunodeficiency ,business.industry ,Spleen ,Pharmacology ,medicine.disease ,Prostate cancer ,medicine.anatomical_structure ,Renal physiology ,Radionuclide therapy ,LNCaP ,Medicine ,Dosimetry ,Radiology, Nuclear Medicine and imaging ,business - Abstract
Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands are applicable as radiochemical twins for both diagnostic PET imaging and endoradiotherapy. On the basis of preliminary data as a diagnostic ligand, the isomer rhPSMA-7.3 is a promising candidate for potential endoradiotherapy. The aim of this preclinical evaluation was to assess the biodistribution, dosimetry, and therapeutic efficacy of 19F/177Lu-rhPSMA-7.3 in comparison to the established therapeutic agent 177Lu-PSMA I&T (imaging and therapy). Methods: The biodistribution of 19F/177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T was determined in LNCaP tumor-bearing severe combined immunodeficiency (SCID) mice after sacrifice at defined time points up to 7 d (n = 5). Organs and tumors were dissected, percentage injected dose per gram (%ID/g) was determined, and dosimetry was calculated using OLINDA/EXM, version 1.0. The therapeutic efficacy of a single 30-MBq dose of 19F/177Lu-rhPSMA-7.3 (n = 7) was compared with that of 177Lu-PSMA I&T in treatment groups (n = 7) and control groups (n = 6-7) using C4-2 tumor-bearing SCID mice by evaluating tumor growth and survival over 6 wk after treatment. Results: The biodistribution of 19F/177Lu-rhPSMA-7.3 revealed fast blood clearance (0.63 %ID/g at 1 h after injection), and the highest activity uptake was in the spleen and kidneys, particularly in the first hour (33.25 %ID/g and 207.6 %ID/g, respectively, at 1 h after injection), indicating a renal excretion pathway. Compared with 177Lu-PSMA I&T, 19F/177Lu-rhPSMA-7.3 exhibited an initial (1 h) 2.6-fold higher tumor uptake in LNCaP xenografts and a longer retention (4.5 %ID/g vs. 0.9 %ID/g at 168 h). The tumor dose of 19F/177Lu-rhPSMA-7.3 was substantially higher (e.g., 7.47 vs. 1.96 µGy/MBq at 200 mm3) than that of 177Lu-PSMA I&T. In most organs, absorbed doses were higher for 177Lu-PSMA I&T. A significantly greater tumor size reduction was shown for a single dose of 19F/177Lu-rhPSMA-7.3 than for 177Lu-PSMA I&T at the end of the experiment (P = 0.0167). At the predefined termination of the experiment at 6 wk, 7 of 7 and 3 of 7 mice were still alive in the 19F/177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T groups, respectively, compared with the respective control groups, with 0 of 7 and 0 of 6 mice. Conclusion: Compared with 177Lu-PSMA I&T, 19F/177Lu-rhPSMA-7.3 can be considered a suitable candidate for clinical translation because it has similar clearance kinetics and a similar radiation dose to healthy organs but superior tumor uptake and retention. Preliminary treatment experiments showed a favorable antitumor response.
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- 2020
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33. Early Prostate-Specific Antigen Changes and Clinical Outcome After 177Lu-PSMA Radionuclide Treatment in Patients with Metastatic Castration-Resistant Prostate Cancer
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Calogero D'Alessandria, Isabel Rauscher, Charlott Franz, Matthias Heck, Wolfgang A. Weber, Matthias Eiber, Andrei Gafita, Lisena Cala, Margitta Retz, and Robert Tauber
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medicine.medical_specialty ,business.industry ,Hazard ratio ,030232 urology & nephrology ,Urology ,urologic and male genital diseases ,Lower risk ,medicine.disease ,03 medical and health sciences ,Prostate-specific antigen ,Prostate cancer ,0302 clinical medicine ,Antigen ,030220 oncology & carcinogenesis ,Radionuclide therapy ,Cohort ,Medicine ,Radiology, Nuclear Medicine and imaging ,business ,Prospective cohort study - Abstract
Prostate-specific antigen (PSA) is widely used to monitor treatment response in patients with metastatic castration-resistant prostate cancer. However, PSA measurements are considered only after 12 wk of treatment. We aimed to evaluate the prognostic value of early PSA changes after 177Lu-labeled prostate-specific membrane antigen (177Lu-PSMA) radionuclide treatment in metastatic castration-resistant prostate cancer patients. Methods: Men who were treated with 177Lu-PSMA under a compassionate-access program at our institution and had available PSA values at baseline and at 6 wk after treatment initiation were included in this retrospective analysis. Patients were assigned to 3 groups on the basis of PSA changes: response (≥30% decline), progression (≥25% increase), and stable (
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- 2020
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34. Room Temperature Al 18 F Labeling of 2‐Aminomethylpiperidine‐Based Chelators for PET Imaging
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Lisa Russelli, Lorenzo Tei, Calogero D'Alessandria, Sybille Reder, Michael Herz, Francesco De Rose, Jonathan Martinelli, Wolfgang A. Weber, and Markus Schwaiger
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Pharmacology ,chemistry.chemical_classification ,medicine.diagnostic_test ,010405 organic chemistry ,Chemistry ,Nacl solutions ,Biomolecule ,Organic Chemistry ,Radiochemistry ,Nuclear magnetic resonance spectroscopy ,Pet imaging ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Positron emission tomography ,Drug Discovery ,medicine ,Molecular Medicine ,Molecule ,Chelation ,General Pharmacology, Toxicology and Pharmaceutics ,Molecular imaging - Abstract
Positron emission tomography (PET) is a non-invasive molecular imaging technology that is constantly expanding, with a high demand for specific antibody-derived imaging probes. The use of tracers based on temperature-sensitive molecules (i. e. Fab, svFab, nanobodies) is increasing and has led us to design a class of chelators based on the structure of 2-aminomethylpiperidine (AMP) with acetic and/or hydroxybenzyl pendant arms (2-AMPTA, NHB-2-AMPDA, and 2-AMPDA-HB), which were investigated as such for {Al18 F}2+ -core chelation efficiency. All the compounds were characterized by HPLC-MS analysis and NMR spectroscopy. The AlF-18 labeling reactions were performed under various conditions (pH/temperature), and the radiolabeled chelates were purified and characterized by radio-TLC and radio-HPLC. The stability of labeled chelates was investigated up to 240 min in human serum (HS), EDTA 5 mM, PBS and 0.9 % NaCl solutions. The in vivo stability of [Al18 F(2-AMPDA-HB)]- was assessed in healthy nude mice (n=6). Radiochemical yields between 55 % and 81 % were obtained at pH 5 and room temperature. High stability in HS was measured for [Al18 F(2-AMPDA-HB)]- , with 90 % of F-18 complexed after 120 min. High stability in vivo, rapid hepatobiliary and renal excretion, with low accumulation of free F-18 in bones were measured. Thus, this new Al18 F-chelator may have a great impact on immuno-PET radiopharmacy, by facilitating the development of new fluorine-18-labeled heat-sensitive biomolecules.
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- 2020
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35. Detection Efficacy of (18)F‐rhPSMA‐7.3 PET/CT and Impact on Management in Patients with Biochemical Recurrence of Prostate Cancer After Radical Prostatectomy and Before Potential Salvage Treatment
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Hannah Worther, Isabel Rauscher, Wolfgang A. Weber, Amir Karimzadeh, Noemi Nguyen, Matthias Eiber, Kilian Schiller, Thomas Horn, Calogero D'Alessandria, Charlott Franz, and Stephanie E. Combs
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Biochemical recurrence ,medicine.medical_specialty ,PET-CT ,medicine.diagnostic_test ,business.industry ,Prostatectomy ,medicine.medical_treatment ,Urology ,Salvage therapy ,medicine.disease ,Prostate cancer ,medicine.anatomical_structure ,Positron emission tomography ,medicine ,Radiology, Nuclear Medicine and imaging ,Lymph ,Clinical Investigation ,business ,Lymph node - Abstract
Purpose: Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands are a new class of 18F-labeled PSMA-targeting agents. 18F-rhPSMA-7.3 is a lead compound which is currently under investigation in two multicenter phase III trials for PET-imaging. Here, we report the first retrospective data on its detection efficacy and potential impact on clinical management in a homogeneous cohort of patients with biochemical recurrence after radical prostatectomy, and prior to any salvage therapy. Methods: 242 patients (median [range] PSA, 0.60 [0.2-60.8] ng/mL) who underwent 18F-rhPSMA-7.3 PET/CT were retrospectively selected from the institutions' database. Images were re-read by an experienced nuclear medicine physician. Lesion detection rates were stratified by PSA. Further, potential management before and after PET was assessed by an interdisciplinary simulated tumor board and categorized (major vs. minor vs. no therapeutic change). The distribution of management change identified in each PSA subgroup was determined. Results: In total, 176/242 (72.7%) patients showed PSMA-ligand positive findings. 18F-rhPSMA-7.3 detection rates were 61.8% (63/102), 67.9% (38/56), 81.1% (30/37) and 95.7% (45/47) for PSA-levels of 0.2
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- 2021
36. Synthesis and Preclinical Evaluation of
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Alexander, Wurzer, Jan-Philip, Kunert, Sebastian, Fischer, Veronika, Felber, Roswitha, Beck, Francesco de, Rose, Calogero, D'Alessandria, Wolfgang, Weber, and Hans-Jürgen, Wester
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Male ,Mice ,Animals ,Humans ,Prostatic Neoplasms ,Urea ,Gallium ,Serum Albumin, Human ,Tissue Distribution ,Ligands - Abstract
The prostate-specific membrane antigen (PSMA)-targeted radiohybrid (rh) ligand [
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- 2021
37. Is Hypoxia a Factor Influencing PSMA-Directed Radioligand Therapy?-An In Silico Study on the Role of Chronic Hypoxia in Prostate Cancer
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Ali Afshar-Oromieh, Volker Morath, Matthias Eiber, Gabriele Birindelli, Milos Drobnjakovic, Wolfgang A. Weber, Calogero D'Alessandria, Kuangyu Shi, Eleni Gourni, Katja Steiger, and Axel Rominger
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Cancer Research ,In silico ,MathematicsofComputing_GENERAL ,610 Medicine & health ,Article ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Prostate ,Radioligand ,medicine ,tumor microenvironment ,convection–reaction–diffusion models ,RC254-282 ,Tumor microenvironment ,Tumor hypoxia ,dosimetry ,Chemistry ,hypoxia ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Hypoxia (medical) ,medicine.disease ,radioligand therapy ,medicine.anatomical_structure ,TheoryofComputation_MATHEMATICALLOGICANDFORMALLANGUAGES ,Oncology ,radiobiology ,030220 oncology & carcinogenesis ,Cancer research ,Immunohistochemistry ,medicine.symptom - Abstract
Radioligand therapy (RLT) targeting prostate specific-membrane antigen (PSMA) is an emerging treatment for metastatic castration-resistant prostate cancer (mCRPC). It administrates 225Ac- or 177Lu-labeled ligands for the targeted killing of tumor cells. Differently from X- or γ-ray, for the emitted α or β particles the ionization of the DNA molecule is less dependent on the tissue oxygenation status. Furthermore, the diffusion range of electrons in a tumor is much larger than the volume typically spanned by hypoxic regions. Therefore, hypoxia is less investigated as an influential factor for PSMA-directed RLT, in particular with β emitters. This study proposes an in silico approach to theoretically investigate the influence of tumor hypoxia on the PSMA-directed RLT. Based on mice histology images, the distribution of the radiopharmaceuticals was simulated with an in silico PBPK-based convection–reaction–diffusion model. Three anti-CD31 immunohistochemistry slices were used to simulate the tumor microenvironment. Ten regions of interest with varying hypoxia severity were analyzed. A kernel-based method was developed for dose calculation. The cell survival probability was calculated according to the linear-quadratic model. The statistical analysis performed on all the regions of interest (ROIs) shows more heterogeneous dose distributions obtained with 225Ac compared to 177Lu. The higher homogeneity of 177Lu-PSMA-ligand treatment is due to the larger range covered by the emitted β particles. The dose-to-tissue histogram (DTH) metric shows that in poorly vascularized ROIs only 10% of radiobiological hypoxic tissue receives the target dose using 177Lu-PSMA-ligand treatment. This percentage drops down to 5% using 225Ac. In highly vascularized ROIs, the percentage of hypoxic tissue receiving the target dose increases to more than 85% and 65% for the 177Lu and 225Ac-PSMA-ligands, respectively. The in silico study demonstrated that the reduced vascularization of the tumor strongly influences the dose delivered by PSMA-directed RLT, especially in hypoxic regions and consequently the treatment outcome.
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- 2021
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38. Preclinical biodistribution and dosimetry and human biodistribution comparing
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Karina, Knorr, So Won, Oh, Markus, Krönke, Alexander, Wurzer, Calogero, D'Alessandria, Michael, Herz, Wolfgang, Weber, Hans-Jürgen, Wester, Matthias, Eiber, Nahid, Yusufi, and Stephan, Nekolla
- Abstract
Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands such asPreclinical dosimetry was performed with SCID-mice sacrificed at multiple timepoints (10-300 min) post-injection of 25.6 ± 3.6 MBqPreclinical dosimetry revealed that at 3.5 h and 1 h bladder voiding intervals, the extrapolated total effective doses were 26.6 and 12.2 µSv/MBq forRadiation dosimetry is favourable for both agents. Radiation exposure, assuming a 1 h voiding interval, is less than 5 mSv after injection of 370 MBq.
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- 2021
39. Radiolabelled cytokines for imaging chronic inflammation
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Alberto Signore, Calogero D'Alessandria, Alessio Annovazzi, and Francesco Scopinaro
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Radiolabelled cytokines ,chronic inflammation ,imaging ,Biotechnology ,TP248.13-248.65 - Abstract
Diagnosis and particularly follow-up of chronic inflammatory disorders could be often difficult in clinical practice. Indeed, traditional radiological techniques reveal only structural tissue alterations and are not able to monitor functional changes occurring in tissues affected by chronic inflammation. The continuous advances in the knowledge of the pathophysioloy of chronic disorders, combined with the progress of radiochemistry, led to the development of new specific radiolabelled agents for the imaging of chronic diseases. In this scenario, cytokines, due to their pivotal role in such diseases, represent good candidates as radiopharmaceuticals.O diagnóstico, e particularmente o acompanhamento das doenças inflamatórias crônicas, pode ser freqüentemente muito difícil na prática clínica. As técnicas radiológicas tradicionais revelam somente as alterações teciduais estruturas, não sendo capazes de monitorar as alterações funcionais que ocorrem nesses tecidos afetados pela inflamação crônica. O contínuo avanço no conhecimento da fisiopatologia dessas doenças, combinado com o progresso da radioquímica, levou ao desenvolvimento de novos agentes radiomarcados para a obtenção de imagens de doenças crônicas. Nesse cenário, as citocinas, devido ao papel primordial em tais doenças, apresentam-se como fortes candidatas a radiofármacos.
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- 2002
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40. Prä-therapeutische Dosimetrie von Lu-177-rhPSMA7.3 und Lu-177-PSMA-I&T bei Patienten mit metastasiertem kastrationsresistentem Prostatakarzinom (mCRPC)
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Benedikt Feuerecker, Matthias Eiber, HJ Wester, M Chantadisai, Isabel Rauscher, Anne Allmann, Jakob Allmann, Robert Tauber, Alexander Wurzer, Wolfgang A. Weber, and Calogero D'Alessandria
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- 2021
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41. Nomograms to predict outcomes after
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Andrei, Gafita, Jeremie, Calais, Tristan R, Grogan, Boris, Hadaschik, Hui, Wang, Manuel, Weber, Shahneen, Sandhu, Clemens, Kratochwil, Rouzbeh, Esfandiari, Robert, Tauber, Anna, Zeldin, Hendrik, Rathke, Wesley R, Armstrong, Andrew, Robertson, Pan, Thin, Calogero, D'Alessandria, Matthew B, Rettig, Ebrahim S, Delpassand, Uwe, Haberkorn, David, Elashoff, Ken, Herrmann, Johannes, Czernin, Michael S, Hofman, Wolfgang P, Fendler, and Matthias, Eiber
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Male ,Nomograms ,Prostatic Neoplasms, Castration-Resistant ,Treatment Outcome ,Humans ,Lutetium ,Prostate-Specific Antigen ,Retrospective Studies - Abstract
Lutetium-177 (In this multicentre, retrospective study, we screened patients with mCRPC who had receivedBetween April 23, 2019, and Jan 13, 2020, 414 patients were screened; 270 (65%) of whom were eligible and were divided into development (n=196) and validation (n=74) cohorts. The median duration of follow-up was 21·5 months (IQR 13·3-30·7). Predictors included in the nomograms were time since initial diagnosis of prostate cancer, chemotherapy status, baseline haemoglobin concentration, and [These externally validated nomograms that are predictive of outcomes afterProstate Cancer Foundation.
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- 2021
42. Development and Validation of Nomograms to Predict Outcome Following LuPSMA Radionuclide Treatment for Metastatic Castration-Resistant Prostate Cancer: A Multicenter International Study
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Andrei Gafita, Jeremie Calais, Tristan R. Grogan, Anna Zeldin, Boris Hadaschik, Wang Hui, Manuel Weber, Shahneen Sandhu, Clemens Kratochwil, Rouzbeh Esfandiari, Robert Tauber, Hendrik Rathke, Wesley R. Armstrong, Andrew Robertson, Pan Thin, Calogero D'Alessandria, Matthew B. Rettig, Ebrahim S. Delpassand, Uwe Haberkorn, David Elashoff, Ken Herrmann, Johannes Czernin, Prof Michael S. Hofman, Wolfgang P. Fendler, and Matthias Eiber
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- 2021
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43. Effective rational humanization of a PASylated anti-galectin-3 Fab for the sensitive PET imaging of thyroid cancer in vivo
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Emanuel Peplau, Francesco De Rose, Andreas Eichinger, Sybille Reder, Markus Mittelhäuser, Giorgia Scafetta, Markus Schwaiger, Wolfgang A. Weber, Armando Bartolazzi, Calogero D’Alessandria, and Arne Skerra
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Science ,Galectins ,Molecular Conformation ,Mice, Nude ,Antibodies, Monoclonal, Humanized ,Crystallography, X-Ray ,Biochemistry ,Article ,Epitopes ,Immunoglobulin Fab Fragments ,Mice ,Protein Domains ,Positron Emission Tomography Computed Tomography ,Animals ,Humans ,Antibody fragment therapy ,Thyroid Neoplasms ,Antibodies, Monoclonal ,Blood Proteins ,Rats ,Kinetics ,Positron-Emission Tomography ,Mutation ,Medicine ,Female ,Zirconium ,Peptides ,Neoplasm Transplantation - Abstract
The lack of a non-invasive test for malignant thyroid nodules makes the diagnosis of thyroid cancer (TC) challenging. Human galectin-3 (hGal3) has emerged as a promising target for medical TC imaging and diagnosis because of its exclusive overexpression in malignant thyroid tissues. We previously developed a human-chimeric αhGal3 Fab fragment derived from the rat monoclonal antibody (mAb) M3/38 with optimized clearance characteristics using PASylation technology. Here, we describe the elucidation of the hGal3 epitope recognized by mAb M3/38, X-ray crystallographic analysis of its complex with the chimeric Fab and, based on the three-dimensional structure, the rational humanization of the Fab by CDR grafting. Four CDR-grafted versions were designed using structurally most closely related fully human immunoglobulin VH/VL regions of which one—employing the acceptor framework regions of the HIV-1 neutralizing human antibody m66—showed the highest antigen affinity. By introducing two additional back-mutations to the rodent donor sequence, an affinity toward hGal3 indistinguishable from the chimeric Fab was achieved (KD = 0.34 ± 0.02 nM in SPR). The PASylated humanized Fab was site-specifically labelled with the fluorescent dye Cy7 and applied for the immuno-histochemical staining of human tissue sections representative for different TCs. The same protein was conjugated with the metal chelator Dfo, followed by radiolabelling with 89Zr(IV). The resulting protein tracer allowed the highly sensitive and specific PET/CT imaging of orthotopic tumors in mice, which was confirmed by quantitative analysis of radiotracer accumulation. Thus, the PASylated humanized αhGal3 Fab offers clinical potential for the diagnostic imaging of TC.
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- 2020
44. Imaging atherosclerotic plaques by targeting Galectin-3 and activated macrophages using (89Zr)-DFO- Galectin3-F(ab')2 mAb
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Wolfgang A. Weber, Dimitris Gorpas, Markus Schwaiger, Sarajo Mohanta, Vasilis Ntziachristos, Calogero D'Alessandria, Armando Bartolazzi, Zohreh Varasteh, Yuanfang Li, Francesco De Rose, Andreas J. R. Habenicht, Hendrik B. Sager, Benedikt Miritsch, Giorgia Scafetta, Changjun Yin, Xi Zhang, and Sarah Glasl
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0301 basic medicine ,Apolipoprotein E ,Pathology ,medicine.medical_specialty ,Atherosclerotic plaques ,PET/CT ,Mice, Knockout, ApoE ,medicine.drug_class ,Galectin 3 ,activated macrophages ,Medicine (miscellaneous) ,Deferoxamine ,030204 cardiovascular system & hematology ,Monoclonal antibody ,Mice ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Gene expression ,medicine ,Galectin-3 ,Animals ,Humans ,Macrophage ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Inflammation ,Radioisotopes ,Chemistry ,CD68 ,Macrophages ,Antibodies, Monoclonal ,Plaque, Atherosclerotic ,ddc ,Mice, Inbred C57BL ,030104 developmental biology ,Positron-Emission Tomography ,Immunohistochemistry ,Female ,Zirconium ,Radiopharmaceuticals ,Immunostaining ,Research Paper - Abstract
Rationale: The high expression of Galectin-3 (Gal3) in macrophages of atherosclerotic plaques suggests its participation in atherosclerosis pathogenesis, and raises the possibility to use it as a target to image disease severity in vivo. Here, we explored the feasibility of tracking atherosclerosis by targeting Gal3 expression in plaques of apolipoprotein E knockout (ApoE-KO) mice via PET imaging. Methods: Targeting of Gal3 in M0-, M1- and M2 (M2a/M2c)-polarized macrophages was assessed in vitro using a Gal3-F(ab')2 mAb labeled with AlexaFluor®488 and 89Zr- desferrioxamine-thioureyl-phenyl-isothiocyanate (DFO). To visualize plaques in vivo, ApoE-KO mice were injected i.v. with 89Zr-DFO-Gal3-F(ab')2 mAb and imaged via PET/CT 48 h post injection. Whole length aortas harvested from euthanized mice were processed for Sudan-IV staining, autoradiography, and immunostaining for Gal3, CD68 and α-SMA expression. To confirm accumulation of the tracer in plaques, ApoE-KO mice were injected i.v. with Cy5.5-Gal3-F(ab')2 mAb, euthanized 48 h post injection, followed by cryosections of the body and acquisition of fluorescent images. To explore the clinical potential of this imaging modality, immunostaining for Gal3, CD68 and α-SMA expression were carried out in human plaques. Single cell RNA sequencing (scRNA-Seq) analyses were performed to measure LGALS3 (i.e. a synonym for Gal3) gene expression in each macrophage of several subtypes present in murine or human plaques. Results: Preferential binding to M2 macrophages was observed with both AlexaFluor®488-Gal3-F(ab')2 and 89Zr-DFO-Gal3-F(ab')2 mAbs. Focal and specific 89Zr-DFO-Gal3-F(ab')2 mAb uptake was detected in plaques of ApoE-KO mice by PET/CT. Autoradiography and immunohistochemical analyses of aortas confirmed the expression of Gal3 within plaques mainly in macrophages. Moreover, a specific fluorescent signal was visualized within the lesions of vascular structures burdened by plaques in mice. Gal3 expression in human plaques showed similar Gal3 expression patterns when compared to their murine counterparts. Conclusions: Our data reveal that 89Zr-DFO-Gal3-F(ab')2 mAb PET/CT is a potentially novel tool to image atherosclerotic plaques at different stages of development, allowing knowledge-based tailored individual intervention in clinically significant disease.
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- 2020
45. Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study
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Clemens Kratochwil, Ken Herrmann, Andrew Robertson, Manuel Weber, Uwe Haberkorn, Ebrahim S. Delpassand, Rouzbeh Esfandiari, Pan Thin, Jeremie Calais, Hui Wang, Andrei Gafita, David Elashoff, Calogero D'Alessandria, Wesley R Armstrong, Tristan Grogan, Boris Hadaschik, Anna Zeldin, Robert Tauber, Johannes Czernin, Hendrik Rathke, Wolfgang P. Fendler, Matthias Eiber, Shahneen Sandhu, Matthew Rettig, and Michael S Hofman
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Oncology ,medicine.medical_specialty ,Chemotherapy ,business.industry ,Proportional hazards model ,Clinical study design ,medicine.medical_treatment ,Retrospective cohort study ,Nomogram ,urologic and male genital diseases ,medicine.disease ,ddc ,Prostate-specific antigen ,Prostate cancer ,Internal medicine ,medicine ,business ,Survival analysis - Abstract
BACKGROUND: Lutetium-177 (177Lu) prostate-specific membrane antigen (177Lu-PSMA) is a novel targeted treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Predictors of outcomes after 177Lu-PSMA to enhance its clinical implementation are yet to be identified. We aimed to develop nomograms to predict outcomes after 177Lu-PSMA in patients with mCRPC. METHODS: In this multicentre, retrospective study, we screened patients with mCRPC who had received 177Lu-PSMA between Dec 10, 2014, and July 19, 2019, as part of the previous phase 2 trials (NCT03042312, ACTRN12615000912583) or compassionate access programmes at six hospitals and academic centres in Germany, the USA, and Australia. Eligible patients had received intravenous 6·0-8·5 GBq 177Lu-PSMA once every 6-8 weeks, for a maximum of four to six cycles, and had available baseline [68Ga]Ga-PSMA-11 PET/CT scan, clinical data, and survival outcomes. Putative predictors included 18 pretherapeutic clinicopathological and [68Ga]Ga-PSMA-11 PET/CT variables. Data were collected locally and centralised. Primary outcomes for the nomograms were overall survival and prostate-specific antigen (PSA)-progression-free survival. Nomograms for each outcome were computed from Cox regression models with LASSO penalty for variable selection. Model performance was measured by examining discrimination (Harrell's C-index), calibration (calibration plots), and utility (patient stratification into low-risk vs high-risk groups). Models were validated internally using bootstrapping and externally by calculating their performance on a validation cohort. FINDINGS: Between April 23, 2019, and Jan 13, 2020, 414 patients were screened; 270 (65%) of whom were eligible and were divided into development (n=196) and validation (n=74) cohorts. The median duration of follow-up was 21·5 months (IQR 13·3-30·7). Predictors included in the nomograms were time since initial diagnosis of prostate cancer, chemotherapy status, baseline haemoglobin concentration, and [68Ga]Ga-PSMA-11 PET/CT parameters (molecular imaging TNM classification and tumour burden). The C-index of the overall survival model was 0·71 (95% CI 0·69-0·73). Similar C-indices were achieved at internal validation (0·71 [0·69-0·73]) and external validation (0·72 [0·68-0·76]). The C-index of the PSA-progression-free survival model was 0·70 (95% CI 0·68-0·72). Similar C-indices were achieved at internal validation (0·70 [0·68-0·72]) and external validation (0·71 [0·68-0·74]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (24·9 months [95% CI 16·8-27·3] vs 7·4 months [4·0-10·8]; p
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- 2020
46. Positive Predictive Value and Correct Detection Rate of
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Maythinee, Chantadisai, Gabriel, Buschner, Markus, Krönke, Isabel, Rauscher, Thomas, Langbein, Stephan G, Nekolla, Kilian, Schiller, Matthias M, Heck, Tobias, Maurer, Alexander, Wurzer, Hans-Juergen, Wester, Calogero, D'Alessandria, Wolfgang, Weber, and Matthias, Eiber
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Male ,Predictive Value of Tests ,Positron Emission Tomography Computed Tomography ,Humans ,Prostatic Neoplasms ,Middle Aged ,Aged ,Retrospective Studies - Abstract
The objective of this retrospective study was to assess the detection rate (DR), positive predictive value (PPV), and correct detection rate (CDR) of
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- 2020
47. Comparative Preclinical Biodistribution, Dosimetry, and Endoradiotherapy in Metastatic Castration-Resistant Prostate Cancer Using
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Nahid, Yusufi, Alexander, Wurzer, Michael, Herz, Calogero, D'Alessandria, Benedikt, Feuerecker, Wolfgang, Weber, Hans-Jürgen, Wester, Stephan, Nekolla, and Matthias, Eiber
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Male ,Mice ,Prostatic Neoplasms, Castration-Resistant ,Animals ,Humans ,Tissue Distribution ,Prostate-Specific Antigen - Abstract
Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands are applicable as radiochemical twins for both diagnostic PET imaging and endoradiotherapy. On the basis of preliminary data as a diagnostic ligand, the isomer rhPSMA-7.3 is a promising candidate for potential endoradiotherapy. The aim of this preclinical evaluation was to assess the biodistribution, dosimetry, and therapeutic efficacy of
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- 2020
48. Development of a Chimeric Antigen-Binding Fragment Directed Against Human Galectin-3 and Validation as an Immuno-Positron Emission Tomography Tracer for the Sensitive
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Emanuel, Peplau, Francesco, De Rose, Sybille, Reder, Markus, Mittelhäuser, Giorgia, Scafetta, Markus, Schwaiger, Wolfgang A, Weber, Armando, Bartolazzi, Arne, Skerra, and Calogero, D'Alessandria
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Hybridomas ,Galectins ,Antibodies, Monoclonal ,Immunoglobulins ,Mice, Nude ,Reproducibility of Results ,Blood Proteins ,Deferoxamine ,Immunohistochemistry ,Recombinant Proteins ,Rats ,Mice ,Cell Line, Tumor ,Immunoglobulin G ,Positron Emission Tomography Computed Tomography ,Positron-Emission Tomography ,Animals ,Humans ,Tissue Distribution ,Thyroid Neoplasms ,Zirconium ,Antigens ,Radionuclide Imaging ,Neoplasm Transplantation - Published
- 2020
49. The effect of attenuation map, scatter energy window width, and volume of interest on the calibration factor calculation in quantitative 177Lu SPECT imaging: Simulation and phantom study
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Wei Bo Li, Calogero D'Alessandria, Alexandra Bartel, Nassir Navab, Sibylle Ziegler, Eric C. Frey, Matthias Eiber, Markus Köhner, Elham Karimi Ghodoosi, Ye Li, and Vera Höllriegl
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Physics ,Photon ,Energy window ,business.industry ,Attenuation ,Monte Carlo method ,Biophysics ,General Physics and Astronomy ,General Medicine ,Imaging phantom ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Optics ,030220 oncology & carcinogenesis ,Spect imaging ,Calibration ,Radiology, Nuclear Medicine and imaging ,business ,Energy (signal processing) - Abstract
Purpose The objective of this study was to evaluate the image degrading factors in quantitative 177Lu SPECT imaging when using both main gamma photopeak energies. Methods Phantom measurements with two different vials containing various calibrated activities in air or water were performed to derive a mean calibration factor (CF) for large and small volumes of interest (VOIs). In addition, Monte Carlo simulations were utilized to investigate the effect of scatter energy window width, scatter correction method, such as effective scatter source estimation (ESSE) and triple energy window (TEW), and attenuation map on the quantification of 177Lu. Results: The measured mean CF using large and small VOIs in water was 4.50 ± 0.80 and 4.80 ± 0.72 cps MBq−1, respectively. Simulations showed a reference CF of 3.3 cps MBq−1 for the water-filled phantom considering all photons excluding scattered events. By using the attenuation map generated for 190 keV photons, the calculated CFs for 113 keV and 208 keV are 10% lower than by using the weighted mean energy of 175 keV for 177Lu. The calculated CF using the TEW correction was 17% higher than using the ESSE method for a water-filled phantom. However, our findings showed that an appropriate scatter window combination can reduce this difference between TEW and ESSE methods. Conclusions The present work implies that choosing a suitable width of scatter energy windows can reduce uncertainties in radioactivity quantification. It is suggested to generate the attenuation map at 113 keV and 208 keV, separately. Furthermore, using small VOIs is suggested in CF calculation.
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- 2018
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50. Early Experience of Rechallenge 177Lu-PSMA Radioligand Therapy After an Initial Good Response in Patients with Advanced Prostate Cancer
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Karina Knorr, Wolfgang A. Weber, Calogero D'Alessandria, Margitta Retz, Robert Tauber, Matthias Heck, Hans-Jürgen Wester, Matthias Eiber, Isabel Rauscher, and Andrei Gafita
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medicine.medical_specialty ,business.industry ,urologic and male genital diseases ,medicine.disease ,Gastroenterology ,Confidence interval ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Antigen ,030220 oncology & carcinogenesis ,Internal medicine ,Toxicity ,Cohort ,Radioligand ,Medicine ,Radiology, Nuclear Medicine and imaging ,business ,Adverse effect ,Progressive disease - Abstract
Our aim was to retrospectively evaluate the feasibility of rechallenge 177Lu-prostate-specific membrane antigen (177Lu-PSMA) radioligand therapy. Methods: Rechallenge radioligand therapy was defined as subsequent treatment with 177Lu-PSMA after initial exposure with an excellent response followed by progression. Biochemical, radiographic, clinical antitumor response, and adverse events were analyzed. Prostate-specific antigen (PSA) progression-free survival (PFS) and overall survival were calculated. Results: Eight patients underwent a median of 2 (range: 1-4) cycles of rechallenge with 177Lu-PSMA for imaging and therapy. A maximum PSA decrease of 50% was achieved in 3 patients (37.5%). Radiographic response was favorable in 3 patients, whereas 4 exhibited progressive disease. Eastern Cooperative Oncology Group performance status was stable during therapy in all patients. No grade 4 toxicity was noticed, and grade 3 toxicity occurred in 3 patients (37.5%). The median PSA-PFS and overall survival were 3.2 mo (95% confidence interval, 2.6-3.7 mo) and 14.0 mo (95% confidence interval, 6.2-21.8 mo), respectively. Conclusion: In a small patient cohort with an initial excellent response, 177Lu-PSMA rechallenge is still active, with lower efficacy and higher toxicity.
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- 2018
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