69 results on '"Bartholomä M"'
Search Results
2. Fully automated multi generator elution for a single synthesis of 68 Ga-labelled compounds using the Trasis mini AIO
- Author
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Maus, S, additional, Bohnenberger, H, additional, Bartholomä, M, additional, Sch㥥r, A, additional, Stemler, T, additional, and Ezziddin, S, additional
- Published
- 2020
- Full Text
- View/download PDF
3. Vergleich verschiedener Methoden zur Bestimmung der radiochemischen Reinheit von [ 225 Ac] Ac- PSMA-617
- Author
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Bohnenberger, H, additional, Stemler, T, additional, Maus, S, additional, Schaefer-Schuler, A, additional, Rosar, F, additional, Ezziddin, S, additional, and Bartholomä, M, additional
- Published
- 2020
- Full Text
- View/download PDF
4. Enzalutamide induces PSMA upregulation in castration-resistant prostate cancer even in patients having previously progressed on enzalutamide
- Author
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Rosar, F, additional, Dewes, S, additional, Ries, M, additional, Khreish, F, additional, Bohnenberger, H, additional, Schaefer-Schuler, A, additional, Maus, S, additional, Linxweiler, J, additional, Bartholomä, M, additional, Ohlmann, C, additional, and Ezziddin, S, additional
- Published
- 2020
- Full Text
- View/download PDF
5. 225 Ac-PSMA-617/ 177 Lu-PSMA-617 Tandem Therapy of Metastatic Castration-Resistant Prostate Cancer: Pilot Experience
- Author
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Khreish, F, additional, Ebert, N, additional, Ries, M, additional, Maus, S, additional, Rosar, F, additional, Bohnenberger, H, additional, Stemler, T, additional, Saar, M, additional, Bartholomä, M, additional, and Ezziddin, S, additional
- Published
- 2020
- Full Text
- View/download PDF
6. Preclinical evaluation of 64Cu-labeled monomeric and trimeric (RGDfK) conjugates based on a novel chelating platform
- Author
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Bartholomä, M., primary, Martin, S., additional, Läppchen, T., additional, Holland, J., additional, and Ezziddin, S., additional
- Published
- 2019
- Full Text
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7. OC-0054: Combination treatment with radiotherapy plus IL-2/anti-IL-2 complexes and its theranostic evaluation
- Author
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Jing, H., primary, Hettich, M., additional, Firat, E., additional, Gaedicke, S., additional, Bartholomä, M., additional, and Niedermann, G., additional
- Published
- 2018
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8. Performance of 111In-PSMA-ligand radioguided surgery for identification of lymph node metastases: Correlation of tracer uptake and histopathology based on 310 single lymph nodes separated from lymphadenectomies in prostate cancer patients
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Schaal, K., primary, Mix, M., additional, Stoykow, C., additional, Bartholomä, M., additional, Drendel, V., additional, Mäcke, H., additional, Gourni, E., additional, Wetterauer, U., additional, Schultze-Seemann, W., additional, Meyer, P.T., additional, and Jilg, C.A., additional
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- 2017
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9. PC#45 - Preclinical evaluation of 64Cu-labeled monomeric and trimeric (RGDfK) conjugates based on a novel chelating platform
- Author
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Bartholomä, M., Martin, S., Läppchen, T., Holland, J., and Ezziddin, S.
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- 2019
- Full Text
- View/download PDF
10. 551 Feasibility of 111In-PSMA-guided surgery for treatment of nodal prostate cancer relapse
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Schaal, K., primary, Stoykow, C., additional, Mix, M., additional, Bartholomä, M., additional, Drendel, V., additional, Mäcke, H., additional, Gourni, E., additional, Wetterauer, U., additional, Schultze-Seemann, W., additional, Meyer, P., additional, and Jilg, C.A., additional
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- 2016
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11. Theranostic Evaluation of the Combination of Hypofractionated Radiation Therapy and IL-2/anti-IL-2 Complexes in Tumor-Bearing Mice
- Author
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Jing, H., Hettich, M., Bartholomae, M., and Niedermann, G.
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- 2017
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- View/download PDF
12. 871 - Performance of 111In-PSMA-ligand radioguided surgery for identification of lymph node metastases: Correlation of tracer uptake and histopathology based on 310 single lymph nodes separated from lymphadenectomies in prostate cancer patients
- Author
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Schaal, K., Mix, M., Stoykow, C., Bartholomä, M., Drendel, V., Mäcke, H., Gourni, E., Wetterauer, U., Schultze-Seemann, W., Meyer, P.T., and Jilg, C.A.
- Published
- 2017
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13. Benefit der implementierten CT-Urographie in die Ga-68-PSMA-11 PET/CT: Erste Resultate in 247 Patienten.
- Author
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Rosar, F, Hügle, MJ, Ries, M, Bartholomä, M, Maus, S, Stemler, T, Khreish, F, and Ezziddin, S
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- 2020
- Full Text
- View/download PDF
14. Fully automated multi generator elution for a single synthesis of68 Ga-labelled compounds using the Trasis mini AIO.
- Author
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Maus, S, Bohnenberger, H, Bartholomä, M, Sch㥥r, A, Stemler, T, and Ezziddin, S
- Published
- 2020
- Full Text
- View/download PDF
15. Enzalutamide induces PSMA upregulation in castration-resistant prostate cancer even in patients having previously progressed on enzalutamide.
- Author
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Rosar, F, Dewes, S, Ries, M, Khreish, F, Bohnenberger, H, Schaefer-Schuler, A, Maus, S, Linxweiler, J, Bartholomä, M, Ohlmann, C, and Ezziddin, S
- Published
- 2020
- Full Text
- View/download PDF
16. Vergleich verschiedener Methoden zur Bestimmung der radiochemischen Reinheit von [225 Ac] Ac- PSMA-617.
- Author
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Bohnenberger, H, Stemler, T, Maus, S, Schaefer-Schuler, A, Rosar, F, Ezziddin, S, and Bartholomä, M
- Published
- 2020
- Full Text
- View/download PDF
17. 225 Ac-PSMA-617/177 Lu-PSMA-617 Tandem Therapy of Metastatic Castration-Resistant Prostate Cancer: Pilot Experience.
- Author
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Khreish, F, Ebert, N, Ries, M, Maus, S, Rosar, F, Bohnenberger, H, Stemler, T, Saar, M, Bartholomä, M, and Ezziddin, S
- Published
- 2020
- Full Text
- View/download PDF
18. Vergleich verschiedener Methoden zur Bestimmung der radiochemischen Reinheit von [ 225 Ac] Ac- PSMA-617
- Author
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Bohnenberger, H, Stemler, T, Maus, S, Schaefer-Schuler, A, Rosar, F, Ezziddin, S, and Bartholomä, M
- Published
- 2020
- Full Text
- View/download PDF
19. 225 Ac-PSMA-617/ 177 Lu-PSMA-617 Tandem Therapy of Metastatic Castration-Resistant Prostate Cancer: Pilot Experience
- Author
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Khreish, F, Ebert, N, Ries, M, Maus, S, Rosar, F, Bohnenberger, H, Stemler, T, Saar, M, Bartholomä, M, and Ezziddin, S
- Published
- 2020
- Full Text
- View/download PDF
20. Outstanding increase in tumor-to-background ratio over time allows tumor localization by [ 89 Zr]Zr-PSMA-617 PET/CT in early biochemical recurrence of prostate cancer.
- Author
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Burgard C, Rosar F, Larsen E, Khreish F, Linxweiler J, Marlowe RJ, Schaefer-Schuler A, Maus S, Petto S, Bartholomä M, and Ezziddin S
- Subjects
- Humans, Male, Retrospective Studies, Aged, Middle Aged, Radioisotopes, Radiopharmaceuticals, Heterocyclic Compounds, 1-Ring, Aged, 80 and over, Positron Emission Tomography Computed Tomography methods, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms pathology, Zirconium, Dipeptides, Neoplasm Recurrence, Local diagnostic imaging, Prostate-Specific Antigen blood
- Abstract
Background: Positron emission tomography/computed tomography (PET/CT) using prostate-specific membrane antigen (PSMA)-targeted radiotracers labeled with zirconium-89 (
89 Zr; half-life ~ 78.41 h) showed promise in localizing biochemical recurrence of prostate cancer (BCR) in pilot studies., Methods: Retrospective analysis of 38 consecutive men with BCR (median [minimum-maximum] prostate-specific antigen 0.52 (0.12-2.50 ng/mL) undergoing [89 Zr]Zr-PSMA-617 PET/CT post-negative [68 Ga]Ga-PSMA-11 PET/CT. PET/CT acquisition 1-h, 24-h, and 48-h post-injection of a median (minimum-maximum) [89 Zr]Zr-PSMA-617 tracer activity of 123 (84-166) MBq., Results: [89 Zr]Zr-PSMA-617 PET/CT detected altogether 57 lesions: 18 local recurrences, 33 lymph node metastases, 6 bone metastases in 30/38 men with BCR (78%) and prior negative conventional PSMA PET/CT. Lesion uptake significantly increased from 1-h to 24-h and, in a majority of cases, from 24-h to 48-h. Tumor-to-background ratios significantly increased over time, with absolute increases of 100 or more. No side effects were noted. After [89 Zr]Zr-PSMA-617 PET/CT-based treatment, prostate-specific antigen concentration decreased in all patients, becoming undetectable in a third of patients., Limitations: retrospective, single center design; infrequent histopathological and imaging verification., Conclusion: This large series provides further evidence that [89 Zr]Zr-PSMA-617 PET/CT is a beneficial imaging modality to localize early BCR. A remarkable increase in tumor-to-background ratio over time allows localization of tumor unidentified on conventional PSMA PET/CT., (© 2024. The Author(s).)- Published
- 2024
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21. Efficacy and safety of rechallenge [ 177 Lu]Lu-PSMA-617 RLT after initial partial remission in patients with mCRPC: evaluation of a prospective registry (REALITY study).
- Author
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Rosar F, Schuler J, Burgard C, Blickle A, Bartholomä M, Maus S, Petto S, Khreish F, Schaefer A, and Ezziddin S
- Abstract
Aim: Rechallenge of [
177 Lu]Lu-PSMA-617 radioligand therapy (RLT) was proposed for patients who initially responded to PSMA-RLT experiencing partial remission, but relapsed into progression after a certain period of remission. However, only limited data is available regarding this approach. In this study, we analyzed the efficacy and safety profile of one or more series of [177 Lu]Lu-PSMA-617 RLT rechallenge in patients from a prospective registry (REALITY Study, NCT04833517) after they initially benefited from PSMA-RLT., Methods: Forty-seven patients with metastatic castration-resistant prostate cancer (mCRPC) who had biochemical response to initial [177 Lu]Lu-PSMA-617 RLT followed by disease progression received at least one (up to three) series of [177 Lu]Lu-PSMA-617 RLT rechallenge. Biochemical response rates based on prostate-specific antigen (PSA) serum value, PSA-based progression-free survival (PFS) and overall survival (OS) were calculated. Adverse events of the treatment were assessed according to 'common terminology criteria for adverse events' (CTCAE)., Results: After one series of RLT rechallenge, a PSA decline of at least 50% was achieved in 27/47 patients (57.4%). The median PFS of all patients was 8.7 mo and the median OS was 22.7 mo, each calculated from the administration of the first rechallenge series. Patients who responded (PSA decline > 50%) to the rechallenge showed a median OS of 27.3 mo. Regarding PFS, a significant correlation (r = 0.4128, p = 0.0323) was found for these patients comparing initial and rechallenge RLT. Ten patients received a second and 3 patients received a third rechallenge series with 8/10 and 3/3 patients responding to repeated RLT rechallenge. No severe deterioration of adverse events rated by CTCAE criteria was observed., Conclusion: [177 Lu]Lu-PSMA-617 RLT rechallenge is associated with significant PSA response and encouraging survival outcome as well as a very favourable safety profile and should therefore be considered as a straight-forward treatment option in mCRPC patients, who previously benefited from PSMA-RLT., (© 2024. The Author(s).)- Published
- 2024
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22. 225 Ac-PSMA-617 Augmentation in High-Risk mCRPC Undergoing 177 Lu-PSMA-617 Radioligand Therapy : Pilot Experience From a Prospective Registry.
- Author
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Rosar F, Burgard C, Rohloff LV, Blickle A, Bartholomä M, Maus S, Petto S, Schaefer-Schuler A, and Ezziddin S
- Subjects
- Humans, Male, Aged, Pilot Projects, Middle Aged, Prospective Studies, Prostate-Specific Antigen blood, Dipeptides therapeutic use, Dipeptides adverse effects, Aged, 80 and over, Ligands, Treatment Outcome, Risk, Actinium, Radioisotopes, Prostatic Neoplasms, Castration-Resistant radiotherapy, Prostatic Neoplasms, Castration-Resistant pathology, Heterocyclic Compounds, 1-Ring therapeutic use, Heterocyclic Compounds, 1-Ring adverse effects, Lutetium, Registries
- Abstract
Purpose: This pilot study investigates the efficacy and safety profile as well as predictive biomarkers of 225 Ac-PSMA-617-augmented 177 Lu-PSMA-617 radioligand therapy (RLT) in a cohort of high-risk patients with metastatic castration-resistant prostate cancer (mCRPC), enrolled in a prospective registry (NCT04833517)., Patients and Methods: A group of n = 33 high-risk mCRPC patients received 177 Lu-PSMA-617 RLT, augmented by 1 or more cycles of 225 Ac-PSMA-617. Response was assessed by prostate-specific antigen (PSA) serum value after 2 cycles of treatment. Overall survival (OS) and PSA-based progression-free survival were evaluated using Kaplan-Meier analysis. To assess the side effect profile, Common Terminology Criteria for Adverse Events were applied. In total, 12 potential pretherapeutic biomarkers were tested for association with OS., Results: The median decrease in serum PSA value was -49.1%, and 16/33 (48.5%) patients experienced a partial response after 2 cycles RLT. The median PSA-based progression-free survival and median OS was 7.2 and 14.8 months, respectively. Alkaline phosphatase ( P < 0.001), lactate dehydrogenase ( P = 0.035), Eastern European Oncology Group Performance Score ( P = 0.037), and the presence of visceral metastases ( P = 0.029) revealed significant association with OS in Kaplan-Meier analysis (log-rank test). Most of the recorded adverse events were rated as mild or moderate. Higher-grade adverse events were very limited with only 1 case (3.0%) of grade 3 anemia. Treatment-related mild xerostomia was recorded in 6/33 (18.2%) patients., Conclusions: 225 Ac-PSMA-617 augmentation in high-risk mCRPC undergoing 177 Lu-PSMA-617 RLT appears to be an effective treatment option with a favorable safety profile. The pretherapeutic values of alkaline phosphatase, lactate dehydrogenase, the Eastern European Oncology Group Performance Score, and the presence of visceral metastases may be appropriate biomarkers predicting survival outcome of this treatment regimen., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2024
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23. Dual FDG/PSMA PET imaging to predict lesion-based progression of mCRPC during PSMA-RLT.
- Author
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Rosar F, Burgard C, David S, Marlowe RJ, Bartholomä M, Maus S, Petto S, Khreish F, Schaefer-Schuler A, and Ezziddin S
- Subjects
- Humans, Male, Aged, Middle Aged, Retrospective Studies, Gallium Radioisotopes, Radiopharmaceuticals, Antigens, Surface metabolism, Glutamate Carboxypeptidase II metabolism, Aged, 80 and over, Lutetium, Prostatic Neoplasms, Castration-Resistant diagnostic imaging, Prostatic Neoplasms, Castration-Resistant pathology, Prostatic Neoplasms, Castration-Resistant metabolism, Prostatic Neoplasms, Castration-Resistant radiotherapy, Fluorodeoxyglucose F18, Positron-Emission Tomography methods, Disease Progression
- Abstract
Candidates for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC) frequently have "mismatch" lesions with pronounced 18-fluorodeoxyglucose ([
18 F]FDG) but attenuated PSMA ligand uptake on positron emission tomography (PET). However, no quantitative criteria yet exist to identify mismatch lesions and predict their response to RLT. To define such criteria, we retrospectively analyzed 267 randomly-selected glucometabolic mCRPC metastases from 22 patients. On baseline PET, we determined [18 F]FDG and [68 Ga]Ga-PSMA-11 maximum standardized uptake value (SUVmax ), and calculated the [18 F]FDG SUVmax /[68 Ga]Ga-PSMA-11 SUVmax quotient (FPQ). From follow-up [18 F]FDG PET after two lutetium-177-PSMA-617 RLT cycles, we evaluated the treatment response and categorized the lesions into three subgroups (partial remission, stable disease, progression) based on change in [18 F]FDG SUVmax . Lastly, we compared the baseline PET variables in progressing versus non-progressing lesions. Variables differing significantly, and a score incorporating them, were assessed via receiver operator characteristic (ROC) curve analysis, regarding ability to predict lesional progression, with area under the curve (AUC) as metric. Cut-offs with optimal sensitivity and specificity were determined using the maximum value of Youden's index. Fifty-one of 267 lesions (19.1%) progressed, 102/267 (38.2%) manifested stable disease, and 114/267 (42.7%) partially responded after two RLT cycles. At baseline, median [68 Ga]Ga-PSMA-11 SUVmax was significantly lower (p < 0.001), median FPQ significantly higher (p < 0.001), and median [18 F]FDG SUVmax similar in progressing versus non-progressing lesions. [68 Ga]Ga-PSMA-11 SUVmax and FPQ showed predictive power regarding progression (AUCs: 0.89, 0.90). An introduced clinical score combining both further improved predictive performance (AUC: 0.94). Optimal cut-offs to foretell progression were: [68 Ga]Ga-PSMA-11 SUVmax < 11.09 (88.2% sensitivity, 81.9% specificity), FPQ ≥ 0.92 (90.2% sensitivity, 78.7% specificity), clinical score ≥ 6/9 points (88.2% sensitivity, 87.5% specificity). At baseline, a low [68 Ga]Ga-PSMA-11 SUVmax and a high FPQ predict early lesional progression under RLT; [18 F]FDG SUVmax does not. A score combining [68 Ga]Ga-PSMA-11 SUVmax and FPQ predicts early lesional progression even more effectively and might therefore be useful to quantitatively identify mismatch lesions., (© 2024. The Author(s).)- Published
- 2024
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24. [ 161 Tb]Tb-PSMA-617 radioligand therapy in patients with mCRPC: preliminary dosimetry results and intra-individual head-to-head comparison to [ 177 Lu]Lu-PSMA-617.
- Author
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Schaefer-Schuler A, Burgard C, Blickle A, Maus S, Petrescu C, Petto S, Bartholomä M, Stemler T, Ezziddin S, and Rosar F
- Subjects
- Male, Humans, Pilot Projects, Radiopharmaceuticals therapeutic use, Dipeptides therapeutic use, Prostate-Specific Antigen, Heterocyclic Compounds, 1-Ring therapeutic use, Radioisotopes therapeutic use, Lutetium, Prostatic Neoplasms, Castration-Resistant radiotherapy, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
Rationale: Evaluation of alternative radionuclides for use in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is currently focusing on
161 Tb, which may provide advantages by emitting additional Auger and conversion electrons. In this pilot study, we present preliminary dosimetry data for [161 Tb]Tb-PSMA-617 RLT in a direct comparison with [177 Lu]Lu-PSMA-617. Method: Six patients with metastatic castration-resistant prostate cancer (mCRPC) underwent treatment with [177 Lu]Lu-PSMA-617 and subsequently - after inadequate response - with [161 Tb]Tb-PSMA-617. Whole-body planar and SPECT imaging-based dosimetry of organs at risk (kidneys and salivary glands) and tumor lesions were calculated using IDAC for177 Lu and OLINDA/EXM for161 Tb. The therapeutic index (TI) of mean tumor-absorbed doses over relevant organs at risk was calculated. Results: Mean absorbed doses to organs at risk of PSMA-RLT were slightly higher for [161 Tb]Tb-PSMA-617 compared to [177 Lu]Lu-PSMA-617 (kidneys: 0.643 ± 0.247 vs. 0.545 ± 0.231 Gy/GBq, factor 1.18; parotid gland: 0.367 ± 0.198 vs. 0.329 ± 0.180 Gy/GBq, factor 1.10), but markedly higher regarding tumor lesions (6.10 ± 6.59 vs 2.59 ± 3.30 Gy/GBq, factor 2.40, p < 0.001). Consequently, the mean TI was higher for [161 Tb]Tb-PSMA-617 compared to [177 Lu]Lu-PSMA-617 for both, the kidneys (11.54 ± 9.74 vs. 5.28 ± 5.13, p = 0.002) and the parotid gland (16.77 ± 13.10 vs. 12.51 ± 18.09, p = 0.008). Conclusion: In this intra-individual head-to-head pilot study, [161 Tb]Tb-PSMA-617 delivered higher tumor-absorbed doses and resulted in superior TI compared to [177 Lu]Lu-PSMA-617. This preliminary data support161 Tb as a promising radionuclide for PSMA-RLT in mCRPC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)- Published
- 2024
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25. [ 89 Zr]Zr-PSMA-617 PET/CT characterization of indeterminate [ 68 Ga]Ga-PSMA-11 PET/CT findings in patients with biochemical recurrence of prostate cancer: lesion-based analysis.
- Author
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Rosar F, Burgard C, Larsen E, Khreish F, Marlowe RJ, Schaefer-Schuler A, Maus S, Petto S, Bartholomä M, and Ezziddin S
- Subjects
- Male, Humans, Gallium Radioisotopes, Retrospective Studies, Neoplasm Recurrence, Local diagnostic imaging, Oligopeptides, Edetic Acid, Positron Emission Tomography Computed Tomography methods, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms pathology, Dipeptides, Heterocyclic Compounds, 1-Ring, Prostate-Specific Antigen
- Abstract
Background: The state-of-the-art method for imaging men with biochemical recurrence of prostate cancer (BCR) is prostate-specific membrane antigen (PSMA)-targeted positron emission tomography/computed tomography (PET/CT) with tracers containing short-lived radionuclides, e.g., gallium-68 (
68 Ga; half-life: ∼67.7 min). However, such imaging not infrequently yields indeterminate findings, which remain challenging to characterize. PSMA-targeted tracers labeled with zirconium-89 (89 Zr; half-life: ∼78.41 h) permit later scanning, which may help in classifying the level of suspiciousness for prostate cancer of lesions previously indeterminate on conventional PSMA-targeted PET/CT., Methods: To assess the ability of [89 Zr]Zr-PSMA-617 PET/CT to characterize such lesions, we retrospectively analyzed altogether 20 lesions that were indeterminate on prior [68 Ga]Ga-PSMA-11 PET/CT, in 15 men with BCR (median prostate-specific antigen: 0.70 ng/mL). The primary endpoint was the lesions' classifications, and secondary endpoints included [89 Zr]Zr-PSMA-617 uptake (maximum standardized uptake value [SUVmax ]), and lesion-to-background ratio (tumor-to-liver ratio of the SUVmax [TLR]). [89 Zr]Zr-PSMA-617 scans were performed 1 h, 24 h, and 48 h post-injection of 123 ± 19 MBq of radiotracer, 35 ± 35 d post-[68 Ga]Ga-PSMA-11 PET/CT., Results: Altogether, 6/20 previously-indeterminate lesions (30%) were classified as suspicious (positive) for prostate cancer, 14/20 (70%), as non-suspicious (negative). In these two categories, [89 Zr]Zr-PSMA-617 uptake and lesional contrast showed distinctly different patterns. In positive lesions, SUVmax and TLR markedly rose from 1 to 48 h, with SUVmax essentially plateauing at high levels, and TLR further steeply increasing, from 24 to 48 h. In negative lesions, uptake, when present, was very low, and decreasing, while contrast was minimal, from 1 to 48 h. No adverse events or clinically-relevant vital signs changes related to [89 Zr]Zr-PSMA-617 PET/CT were noted during or ~ 4 weeks after the procedure., Conclusions: In men with BCR, [89 Zr]Zr-PSMA-617 PET/CT may help characterize as suspicious or non-suspicious for prostate cancer lesions that were previously indeterminate on [68 Ga]Ga-PSMA-11 PET/CT., Trial Registration: Not applicable., (© 2024. The Author(s).)- Published
- 2024
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26. Change in total lesion PSMA (TLP) during [ 177 Lu]Lu-PSMA-617 radioligand therapy predicts overall survival in patients with mCRPC: monocentric evaluation of a prospective registry.
- Author
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Burgard C, Hein C, Blickle A, Bartholomä M, Maus S, Petto S, Schaefer-Schuler A, Ezziddin S, and Rosar F
- Subjects
- Male, Humans, Positron Emission Tomography Computed Tomography methods, Retrospective Studies, Dipeptides therapeutic use, Heterocyclic Compounds, 1-Ring therapeutic use, Treatment Outcome, Lutetium therapeutic use, Prostate-Specific Antigen, Prostatic Neoplasms, Castration-Resistant radiotherapy, Prostatic Neoplasms, Castration-Resistant pathology, Gallium Radioisotopes
- Abstract
Purpose: This study investigates imaging response of [
177 Lu]Lu-PSMA-617 radioligand therapy (RLT) based on the whole-body parameter total lesion PSMA (TLP), derived by PSMA-PET/CT and reflecting the total tumor burden, in patients with metastatic castration-resistant prostate cancer (mCRPC) enrolled in a prospective registry (NCT04833517)., Methods: A total of n = 102 mCRPC patients received a [68 Ga]Ga-PSMA-11 PET/CT at baseline and after two cycles of PSMA-RLT, in which TLP was measured by using a semi-automated tumor segmentation. TLP was defined as the summed products of volume and uptake (∑ Volume × SUVmean ) of all tumor lesions. The Kaplan-Meier method was used to determine the most appropriate ∆TLP thresholds for classification into partial remission (PR), stable disease (SD), and progressive disease (PD) regarding overall survival (OS). Furthermore, we analyzed criteria that are also frequently used in established response frameworks, such as the occurrence of new metastases as independent criterion (I) or in combination with change in tumor burden (II), and the change in PSA serum value (III)., Results: For the ∆TLP thresholds -30%/+30% (and also for higher thresholds, -40%/+40% or -50%/+50%), significant differences between all three response categories became apparent (PR/PD: p = 0.001; PR/SD: p = 0.001; SD/PD: p = 0.018). Including the development of new metastases as independent criterion of PD, there was no significant difference in OS between SD and PD (p = 0.455), neither when applied in combination with TLP (p = 0.191). Similarly, significant differentiation between SD and PD was not achieved by PSA serum value (p = 0.973)., Conclusion: In the largest monocentric study to date, TLP is shown to be a qualified prognostic biomarker, applying ∆TLP thresholds of -30%/+30%. It significantly differentiated between PR, SD, and PD, whereas other response criteria did not differentiate SD vs. PD. Using TLP, the development of new metastases is not a required information for predicting OS., (© 2023. The Author(s).)- Published
- 2024
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27. Change of glucometabolic activity per PSMA expression predicts survival in mCRPC patients non-responding to PSMA radioligand therapy: introducing a novel dual imaging biomarker.
- Author
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Burgard C, Engler J, Blickle A, Bartholomä M, Maus S, Schaefer-Schuler A, Khreish F, Ezziddin S, and Rosar F
- Abstract
Purpose: The value of [
18 F]fluorodeoxyglucose ([18 F]FDG) PET/CT in monitoring prostate-specific membrane antigen (PSMA) targeted radioligand therapy (RLT) is still unclear. The aim of this study was to identify appropriate prognostic dynamic parameters derived from baseline and follow-up [18 F]FDG and dual [18 F]FDG/[68 Ga]Ga-PSMA-11 PET/CT for monitoring early non-responding mCRPC patients undergoing PSMA-RLT., Methods: Twenty-three mCRPC patients of a prospective registry (NCT04833517), who were treated with [177 Lu]Lu-PSMA-617 RLT and classified as early non-responders were included in this study. All patients received dual PET/CT imaging with [18 F]FDG and [68 Ga]Ga-PSMA-11 at baseline and after median two cycles of RLT. We tested potential biomarkers representing the " change of glucometabolic activity (cGA) " and " change of glucometabolic activity in relation to PSMA expression (cGAP) " composed of established parameters on [18 F]FDG PET/CT as SUVmax, cumulative SUV of five lesions (SUV5), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) and its corresponding parameters on [68 Ga]Ga-PSMA-11 PET/CT, respectively, for association with overall survival (OS)., Results: Kaplan-Meier analyses showed no significant association with OS for each tested cGA (cGASUVmax p = 0.904, cGASUV5 , p = 0.747 cGAMTV p = 0.682 and cGATLG p = 0.700), likewise the dual imaging biomarkers cGAPSUVmax ( p = 0.136), cGAPSUV5 ( p = 0.097), and cGAPTV ( p = 0.113) failed significance. In contrast, cGAPTL , which is based on TLG and total lesion PSMA (TLP) showed a significant association with OS ( p = 0.004). Low cGAPTL (cut-off 0.7) was associated with significant longer survival (17.6 vs. 12.9 months)., Conclusion: The novel biomarker cGAPTL , which represents the temporal change of whole-body TLG normalized by TLP, predicts overall survival in the challenging cohort of patients non-responding to PSMA-RLT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Burgard, Engler, Blickle, Bartholomä, Maus, Schaefer-Schuler, Khreish, Ezziddin and Rosar.)- Published
- 2024
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28. Detection efficacy of [ 89 Zr]Zr-PSMA-617 PET/CT in [ 68 Ga]Ga-PSMA-11 PET/CT-negative biochemical recurrence of prostate cancer.
- Author
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Rosar F, Khreish F, Marlowe RJ, Schaefer-Schuler A, Burgard C, Maus S, Petto S, Bartholomä M, and Ezziddin S
- Subjects
- Male, Humans, Positron Emission Tomography Computed Tomography methods, Gallium Radioisotopes, Prospective Studies, Retrospective Studies, Neoplasm Recurrence, Local diagnostic imaging, Neoplasm Recurrence, Local pathology, Recurrence, Prostate-Specific Antigen, Prostatic Neoplasms pathology
- Abstract
Rationale: In patients with biochemical recurrence of prostate cancer (BCR), preliminary data suggest that prostate-specific membrane antigen (PSMA) ligand radiotracers labeled with zirconium-89 (
89 Zr; half-life ~ 78.41 h), which allow imaging ≥ 24 h post-injection, detect suspicious lesions that are missed when using tracers incorporating short-lived radionuclides., Materials and Methods: To confirm [89 Zr]Zr-PSMA-617 positron emission tomography/computed tomography (PET/CT) detection efficacy regarding such lesions, and compare quality of 1-h, 24-h, and 48-h [89 Zr]Zr-PSMA-617 scans, we retrospectively analyzed visual findings and PET variables reflecting lesional [89 Zr]Zr-PSMA-617 uptake and lesion-to-background ratio. The cohort comprised 23 men with BCR post-prostatectomy, median (minimum-maximum) prostate-specific antigen (PSA) 0.54 (0.11-2.50) ng/mL, and negative [68 Ga]Ga-PSMA-11 scans 40 ± 28 d earlier. Primary endpoints were percentages of patients with, and classifications of, suspicious lesions., Results: Altogether, 18/23 patients (78%) had 36 suspicious lesions (minimum-maximum per patient: 1-4) on both 24-h and 48-h scans (n = 33 lesions) or only 48-h scans (n = 3 lesions). Only one lesion appeared on a 1-h scan. Lesions putatively represented local recurrence in 11 cases, and nodal or bone metastasis in 21 or 4 cases, respectively; 1/1 lesion was histologically confirmed as a nodal metastasis. In all 15 patients given radiotherapy based on [89 Zr]Zr-PSMA-617 PET/CT, PSA values decreased after this treatment. Comparison of PET variables in 24-h vs 48-h scans suggested no clear superiority of either regarding radiotracer uptake, but improved lesion-to-background ratio at 48 h., Conclusions: In men with BCR and low PSA, [89 Zr]Zr-PSMA-617 PET/CT seems effective in finding prostate malignancy not seen on [68 Ga]Ga-PSMA-11 PET/CT. The higher detection rates and lesion-to-background ratios of 48-h scans versus 24-h scans suggest that imaging at the later time may be preferable. Prospective study of [89 Zr]Zr-PSMA-617 PET/CT is warranted., (© 2023. The Author(s).)- Published
- 2023
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29. Tumor Sink Effect with Prostate-Specific Membrane Antigen-Targeted Theranostics in Patients with Metastatic Castration-Resistant Prostate Cancer: Intra-Individual Evaluations.
- Author
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Burgard C, Rosar F, Marlowe RJ, Bartholomä M, Dewes S, Schaefer-Schuler A, Linxweiler J, Khreish F, and Ezziddin S
- Abstract
"Tumor sink effects", decreased physiological uptake of radiopharmaceuticals due to sequestration by a tumor, may impact radioligand therapy (RLT) toxicity and dosing. We investigated these effects with prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals in the healthy organs-at-risk (the parotid glands, kidneys, liver, and spleen) of 33 patients with metastatic castration-resistant prostate cancer (mCRPC). We retrospectively performed three intra-individual comparisons. First, we correlated changes from baseline to post-RLT (after two 177-lutetium (177Lu)-PSMA-617 cycles) in total lesional PSMA (∆TLP) and organ mean standardized uptake values (∆SUVmean). Second, in 25 RLT responders, we compared the organ SUVmean post-RLT versus that at baseline. Lastly, we correlated the baseline TLP and organ SUVmean. Data were acquired via 68-gallium-PSMA-11 positron emission tomography before the first and after the second 177Lu-PSMA-617 cycle. In the parotid glands and spleen, ∆TLP and ∆SUVmean showed a significant inverse correlation (r = -0.40, p = 0.023 and r = -0.36, p = 0.042, respectively). Additionally, in those tissues, the median organ SUVmean rose significantly from baseline after the response to RLT ( p ≤ 0.022), and the baseline TLP and SUVmean were significantly negatively correlated (r = -0.44, p = 0.01 and r = -0.42, p = 0.016, respectively). These observations suggest tumor sink effects with PSMA-targeted radiopharmaceuticals in the salivary glands and spleen of patients with mCRPC.
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- 2023
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30. [ 89 Zr]Zr-PSMA-617 PET/CT in biochemical recurrence of prostate cancer: first clinical experience from a pilot study including biodistribution and dose estimates.
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Rosar F, Schaefer-Schuler A, Bartholomä M, Maus S, Petto S, Burgard C, Privé BM, Franssen GM, Derks YHW, Nagarajah J, Khreish F, and Ezziddin S
- Subjects
- Male, Humans, Gallium Radioisotopes, Tissue Distribution, Pilot Projects, Radioisotopes, Positron Emission Tomography Computed Tomography methods, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms pathology
- Abstract
Purpose: Prostate-specific membrane antigen (PSMA)-targeted PET/CT has become increasingly important in the management of prostate cancer, especially in localization of biochemical recurrence (BCR). PSMA-targeted PET/CT imaging with long-lived radionuclides as
89 Zr (T1/2 = 78.4 h) may improve diagnostics by allowing data acquisition on later time points. In this study, we present our first clinical experience including preliminary biodistribution and dosimetry data of [89 Zr]Zr-PSMA-617 PET/CT in patients with BCR of prostate cancer., Methods: Seven patients with BCR of prostate cancer who revealed no (n = 4) or undetermined (n = 3) findings on [68 Ga]Ga-PSMA-11 PET/CT imaging were referred to [89 Zr]Zr-PSMA-617 PET/CT. PET/CT imaging was performed 1 h, 24 h, 48 h, and 72 h post injection (p.i.) of 111 ± 11 MBq [89 Zr]Zr-PSMA-617 (mean ± standard deviation). Normal organ distribution and dosimetry were determined. Lesions visually considered as suggestive of prostate cancer were quantitatively analyzed., Results: Intense physiological uptake was observed in the salivary and lacrimal glands, liver, spleen, kidneys, intestine and urinary tract. The parotid gland received the highest absorbed dose (0.601 ± 0.185 mGy/MBq), followed by the kidneys (0.517 ± 0.125 mGy/MBq). The estimated overall effective dose for the administration of 111 MBq was 10.1 mSv (0.0913 ± 0.0118 mSv/MBq). In 6 patients, and in particular in 3 of 4 patients with negative [68 Ga]Ga-PSMA-11 PET/CT, at least one prostate cancer lesion was detected in [89 Zr]Zr-PSMA-617 PET/CT imaging at later time points. The majority of tumor lesions were first visible at 24 h p.i. with continuously increasing tumor-to-background ratio over time. All tumor lesions were detectable at 48 h and 72 h p.i., Conclusion: [89 Zr]Zr-PSMA-617 PET/CT imaging is a promising new diagnostic tool with acceptable radiation exposure for patients with prostate cancer especially when [68 Ga]Ga-PSMA-11 PET/CT imaging fails detecting recurrent disease. The long half-life of89 Zr enables late time point imaging (up to 72 h in our study) with increased tracer uptake in tumor lesions and higher tumor-to-background ratios allowing identification of lesions non-visible on [68 Ga]Ga-PSMA-11 PET/CT imaging., (© 2022. The Author(s).)- Published
- 2022
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31. Benefit of including CT urography in [68Ga]PSMA-11 PET/CT with low-dose CT: first results from a larger prostate cancer cohort analysis.
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Rosar F, Hügle MJ, Ries M, Bartholomä M, Maus S, Fries P, Khreish F, and Ezziddin S
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- Gallium Radioisotopes, Humans, Lymphatic Metastasis, Male, Retrospective Studies, Urography, Positron Emission Tomography Computed Tomography methods, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms pathology
- Abstract
Background: Accuracy of [
68 Ga]PSMA-11 PET/CT may be hampered by ureter accumulation, mimicking lymph node metastases depending on localization and configuration. The benefit of CT urography for differentiation of lymph node metastasis from urinary tract activity was evaluated in a "PET/CT with low-dose CT" setting., Methods: Retrospective analysis of PET/CT for primary staging, biochemical recurrence or local treatment planning in patients with prostate cancer. For CT urography (CTU), iodinated contrast agent was administered 10 minutes prior to image acquisition. All potential pathologic (peri)ureteral tracer uptake was assigned to excretory ureteral accumulation or pathological lesion. To assess additional provided benefit of CTU all foci were rated with an introduced scoring system (ranging from 0 pts: CTU not needed; up to 3 pts: no differentiation possible without CTU). Success of ureter contrasting was assessed by measurement of Hounsfield units. Besides benefit for reading urography-enhanced PET/CT, the possible impact on subsequent patient treatment was evaluated., Results: A number of N.=247 patients were included in this study. By CT urography, it was possible to identify each ureter on low-dose CT, with its major part contrasted. In 120/247 (48.6%) patients, urography increased the diagnostic confidence while providing substantial support for interpretation in 60 (24.3%) cases. In 42 (17.0%) patients, urography was clinically relevant (up-/downstaging) with potential impact on subsequent patient care. In 30 of these 42 cases (12.1% of all), discrepant treatment would have resulted from a misdiagnosed tracer accumulation without urography., Conclusions: CT urography benefits the interpretation of [68 Ga]-PSMA-11 PET/CT with low-dose CT and leads to discrepant patient treatment in a small but significant subset of patients (12% in our cohort). The implementation of CT urography into standard protocols of [68 Ga]PSMA-11 PET/CT with low-dose CT is recommended.- Published
- 2022
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32. Bioconjugated chelates based on (methylpyridinyl)tacn: synthesis, 64Cu labeling and in vitro evaluation for prostate cancer targeting.
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Marlin A, Hierlmeier I, Guillou A, Bartholomä M, Tripier R, and Patinec V
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- Chelating Agents, Copper Radioisotopes, Humans, Male, Peptides, Bombesin, Prostatic Neoplasms
- Abstract
Three new bifunctional copper chelators based on the 1,4,7-triazacyclononane (tacn) platform have been synthesized and conjugated to peptides. The first one is constituted of the tacn with two methylpyridinyl and one methylthiazolyl carboxylic acid pendant arms, while, in the second and third ones, the macrocycle is functionalized by three methylpyridinyl groups, with an additional hexynoic acid chain on a carbon of one or two pyridine rings. These three bifunctional chelators have been conjugated to the antagonist DPhe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 peptide for targeting the gastrin-releasing peptide receptor, which is overexpressed in prostate cancer. The resulting monomeric bioconjugates have shown their efficiency to be radiolabeled with β+ emitter 64Cu, and the hydrophilicity and PC-3 cell internalization properties of these radiolabeled conjugates have been studied. PC-3 cell binding affinity of mono- and dimeric metal-free and natCu metallated conjugates have been evaluated by IC50 measurements. The results demonstrate the potential of these methylpyridinyl tacn derivatives for radiopharmaceutical applications., (© The Author(s) 2022. Published by Oxford University Press.)
- Published
- 2022
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33. Addition of Standard Enzalutamide Medication Shows Synergistic Effects on Response to [ 177 Lu]Lu-PSMA-617 Radioligand Therapy in mCRPC Patients with Imminent Treatment Failure-Preliminary Evidence of Pilot Experience.
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Rosar F, Bader H, Bartholomä M, Maus S, Burgard C, Linxweiler J, Khreish F, and Ezziddin S
- Abstract
Well-received strong efficacy of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) does not prevent patients from either early or eventual disease progression under this treatment. In this study, we investigated co-medication with enzalutamide as a potential re-sensitizer for PSMA-RLT in patients with imminent treatment failure on standard
177 Lu-based PSMA-RLT. Ten mCRPC patients who exhibited an insufficient response to conventional [177 Lu]Lu-PSMA-617 RLT received oral medication of enzalutamide 160 mg/d as an adjunct to continued PSMA-RLT. Prostate-specific antigen (PSA) and standard toxicity screening lab work-up were performed to assess the treatment efficacy and safety in these individuals. The mean PSA increase under PSMA-RLT before starting the re-sensitizing procedure was 22.4 ± 26.5%. After the introduction of enzalutamide medication, all patients experienced a PSA decrease, -43.4 ± 20.0% and -48.2 ± 39.0%, after one and two cycles of enzalutamide-augmented PSMA-RLT, respectively. A total of 70% of patients (7/10) experienced partial remission, with a median best PSA response of -62%. Moreover, 5/6 enzalutamide-naïve patients and 2/4 patients who had previously failed enzalutamide exhibited a partial remission. There was no relevant enzalutamide-induced toxicity observed in this small cohort. This pilot experience suggests the synergistic potential of adding enzalutamide to PSMA-RLT derived from the intra-individual comparison of177 Lu-based PSMA-RLT ± enzalutamide.- Published
- 2022
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34. 89 Zr-labeled PSMA ligands for pharmacokinetic PET imaging and dosimetry of PSMA-617 and PSMA-I&T: a preclinical evaluation and first in man.
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Privé BM, Derks YHW, Rosar F, Franssen GM, Peters SMB, Khreish F, Bartholomä M, Maus S, Gotthardt M, Laverman P, Konijnenberg MW, Ezziddin S, Nagarajah J, and Heskamp S
- Subjects
- Animals, Cell Line, Tumor, Dipeptides, Heterocyclic Compounds, 1-Ring, Humans, Ligands, Mice, Mice, Nude, Positron-Emission Tomography methods, Prostate-Specific Antigen, Radioisotopes, Radiopharmaceuticals pharmacokinetics, Tissue Distribution, Lutetium, Positron Emission Tomography Computed Tomography methods
- Abstract
Rationale: Prolonged in vivo evaluation of PSMA tracers could improve tumor imaging and patient selection for
177 Lu-PSMA-617 and177 Lu-PSMA-I&T. In this study, we present the radiolabeling method of PSMA-617 and PSMA-I&T with the long-lived positron emitter89 Zr to enable PET imaging up to 7 days post-injection. We compared the biodistribution of89 Zr-PSMA-617 and89 Zr-PSMA-I&T to those of177 Lu-PSMA-617 and177 Lu-PSMA-I&T, respectively, in a PSMA+ xenograft model. Moreover, we provide the first human89 Zr-PSMA-617 images., Materials and Methods: PSMA ligands were labeled with 50-55 MBq [89 Zr]ZrCl4 using a two-step labeling protocol. For biodistribution, BALB/c nude mice bearing PSMA+ and PSMA- xenografts received 0.6 µg (0.6-1 MBq) of89 Zr-PSMA-617,89 Zr-PSMA-I&T,177 Lu-PSMA-617, or177 Lu-PSMA-I&T intravenously. Ex vivo biodistribution and PET/SPECT imaging were performed up to 168 h post-injection. Dosimetry was performed from the biodistribution data. The patient received 90.5 MBq89 Zr-PSMA-617 followed by PET/CT imaging., Results:89 Zr-labeled PSMA ligands showed a comparable ex vivo biodistribution to its respective177 Lu-labeled counterparts with high tumor accumulation in the PSMA+ xenografts. However, using a dose estimation model for177 Lu, absorbed radiation dose in bone and kidneys differed among the177 Lu-PSMA and89 Zr-PSMA tracers.89 Zr-PSMA-617 PET in the first human patient showed high contrast of PSMA expressing tissues up to 48 h post-injection., Conclusion: PSMA-617 and PSMA-I&T were successfully labeled with89 Zr and demonstrated high uptake in PSMA+ xenografts, which enabled PET up to 168 h post-injection. The biodistribution of89 Zr-PSMA-I&T and89 Zr-PSMA-617 resembled that of177 Lu-PSMA-I&T and177 Lu-PSMA-617, respectively. The first patient89 Zr-PSMA-617 PET images were of high quality warranting further clinical investigation., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2022
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35. 89Zr-PSMA-617 PET/CT May Reveal Local Recurrence of Prostate Cancer Unidentified by 68Ga-PSMA-11 PET/CT.
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Rosar F, Bartholomä M, Maus S, Privé BM, Khreish F, Franssen GM, Derks YHW, Nagarajah J, and Ezziddin S
- Subjects
- Aged, Dipeptides, Edetic Acid, Gallium Isotopes, Gallium Radioisotopes, Heterocyclic Compounds, 1-Ring, Humans, Male, Neoplasm Recurrence, Local diagnostic imaging, Prostate-Specific Antigen, Radioisotopes, Zirconium, Positron Emission Tomography Computed Tomography methods, Prostatic Neoplasms diagnostic imaging
- Abstract
Abstract: For localization of biochemical recurrence of prostate cancer, 68Ga-PSMA-11 PET/CT imaging was performed in a 66-year-old man with no suspicious findings at 1 hour p.i. Additional 89Zr-PSMA-617 PET/CT revealed a small local recurrence in the prostate bed, facilitating consecutive local therapy. This interesting image points to the potential of PET/CT with 89Zr-labeled PSMA ligands, for example, 89Zr-PSMA-617, for identifying the source of biochemical recurrence despite otherwise negative imaging including conventional PSMA PET/CT., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2022
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36. Early molecular imaging response assessment based on determination of total viable tumor burden in [ 68 Ga]Ga-PSMA-11 PET/CT independently predicts overall survival in [ 177 Lu]Lu-PSMA-617 radioligand therapy.
- Author
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Rosar F, Wenner F, Khreish F, Dewes S, Wagenpfeil G, Hoffmann MA, Schreckenberger M, Bartholomä M, and Ezziddin S
- Subjects
- Dipeptides therapeutic use, Gallium Radioisotopes, Heterocyclic Compounds, 1-Ring therapeutic use, Humans, Lutetium, Male, Molecular Imaging, Positron Emission Tomography Computed Tomography methods, Prospective Studies, Retrospective Studies, Treatment Outcome, Tumor Burden, Prostate-Specific Antigen, Prostatic Neoplasms, Castration-Resistant diagnostic imaging, Prostatic Neoplasms, Castration-Resistant pathology, Prostatic Neoplasms, Castration-Resistant radiotherapy
- Abstract
Purpose: In patients with metastatic castration-resistant prostate cancer (mCRPC) treated with prostate-specific membrane antigen-targeted radioligand therapy (PSMA-RLT), the predictive value of PSMA PET/CT-derived response is still under investigation. Early molecular imaging response based on total viable tumor burden and its association with overall survival (OS) was explored in this study., Methods: Sixty-six mCRPC patients who received [
177 Lu]Lu-PSMA-617 RLT within a prospective patient registry (REALITY Study, NCT04833517) were analyzed. Patients received a [68 Ga]Ga-PSMA-11 PET/CT scan before the first and after the second cycle of PSMA-RLT. Total lesion PSMA (TLP) was determined by semiautomatic whole-body tumor segmentation. Molecular imaging response was assessed by change in TLP and modified PERCIST criteria. Biochemical response was assessed using standard serum PSA and PCWG3 criteria. Both response assessment methods and additional baseline parameters were analyzed regarding their association with OS by univariate and multivariable analysis., Results: By molecular imaging, 40/66 (60.6%) patients showed partial remission (PR), 19/66 (28.7%) stable disease (SD), and 7/66 (10.6%) progressive disease (PD). Biochemical response assessment revealed PR in 34/66 (51.5%) patients, SD in 20/66 (30.3%), and PD in 12/66 (18.2%). Response assessments were concordant in 49/66 (74.3%) cases. On univariate analysis, both molecular and biochemical response (p = 0.001 and 0.008, respectively) as well as two baseline characteristics (ALP and ECOG) were each significantly associated with OS. The median OS of patients showing molecular PR was 24.6 versus 10.7 months in the remaining patients (with SD or PD). On multivariable analysis molecular imaging response remained an independent predictor of OS (p = 0.002), eliminating biochemical response as insignificant (p = 0.515)., Conclusion: The new whole-body molecular imaging-derived biomarker, early change of total lesion PSMA (TLP), independently predicts overall survival in [177 Lu]Lu-PSMA-617 RLT in mCRPC, outperforming conventional PSA-based response assessment. TLP might be considered a more distinguished and advanced biomarker for monitoring PSMA-RLT over commonly used serum PSA., (© 2021. The Author(s).)- Published
- 2022
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37. Upregulation of PSMA Expression by Enzalutamide in Patients with Advanced mCRPC.
- Author
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Rosar F, Neher R, Burgard C, Linxweiler J, Schreckenberger M, Hoffmann MA, Bartholomä M, Khreish F, and Ezziddin S
- Abstract
In this study, we investigated upregulation of prostate-specific membrane antigen (PSMA) by enzalutamide in a cohort (n = 30) of patients with advanced metastatic castration-resistant prostate cancer (mCRPC). Patients were examined by [68Ga]Ga-PSMA-11 PET/CT pre- and post-enzalutamide medication (mean 13 ± 7 days). Imaging results were compared based on quantification of whole-body PSMA tumor burden: total lesion PSMA (TLP) and normalized TLP values to liver (TLP-LR) and to parotid gland (TLP-PR). In addition, lesion-based analyses were performed. The median (mean) increases in TLP, TLP-LR and TLP-PR after enzalutamide medication were 10.1% (20.2%), 29.5% (34.8%) and 27.6% (24.4%), respectively. These increases were statistically significant (p = 0.002, p < 0.001, and p < 0.001), while prostate-specific antigen (PSA) serum values did not change significantly (p = 0.483). The increase was independent of prior patient exposure to enzalutamide. SUVmax increased substantially (>10%) in 49.6% of target lesions. The relative change was significantly higher in the subgroup of lesions with SUVmax < 10 (p < 0.001). In conclusion, short-term enzalutamide medication significantly increases PSMA expression in patients with mCRPC, irrespective of prior enzalutamide exposure. The relative PSMA upregulation effect seems to be more pronounced in lesions with only moderate baseline PSMA expression. Enzalutamide may provide a potential enhancer medication for PSMA-targeted radioligand therapy.
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- 2022
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38. 177 Lu-PSMA-617 radioligand therapy of metastatic castration-resistant prostate cancer: Initial 254-patient results from a prospective registry (REALITY Study).
- Author
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Khreish F, Ghazal Z, Marlowe RJ, Rosar F, Sabet A, Maus S, Linxweiler J, Bartholomä M, and Ezziddin S
- Subjects
- Aged, Dipeptides adverse effects, Heterocyclic Compounds, 1-Ring adverse effects, Humans, Lutetium therapeutic use, Male, Prospective Studies, Prostate-Specific Antigen, Radioisotopes, Registries, Retrospective Studies, Treatment Outcome, Prostatic Neoplasms, Castration-Resistant pathology, Prostatic Neoplasms, Castration-Resistant radiotherapy
- Abstract
Purpose: Preliminary data from retrospective analyses and recent data from large randomized controlled trials suggest safety and efficacy of radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) in men with metastatic castration-resistant prostate cancer (mCRPC). Limited data on this modality have been published regarding large samples treated in everyday practice., Methods: We analyzed prospectively collected registry data regarding lutetium-177 (
177 Lu)-PSMA-617 RLT of 254 consecutive men with mCRPC seen in everyday academic practice. Since177 Lu-PSMA-617 was experimental salvage treatment following failure of individually appropriate conventional therapies, patients were generally elderly and heavily pretreated (median age 70 years; prior taxanes 74.0%, 188/254), with late-end-stage disease (visceral metastasis in 32.7%, 83/254). Primary endpoints were response to RLT, defined by changes from baseline serum prostate-specific antigen (PSA) concentration, PSA progression-free survival (PSA-PFS), and overall survival (OS), estimated with Kaplan-Meier statistics, and caregiver-reported and patient-reported safety. Unless noted, median (minimum-maximum) values are given., Results: Patients received 3 (1-13)177 Lu-PSMA-617 activities (6.5 [2.5-11.6] GBq/cycle) every 5.7 (3.0-11.0) weeks. Best response was ≥ 50% PSA reduction in 52.0% of patients (132/254). PSA-PFS was 5.5 (95% confidence interval [95%CI] 4.4-6.6) months and OS, 14.5 (95%CI 11.5-17.5) months. In multivariable Cox proportional-hazards modeling, response to the initial ≤ 2 RLT administrations was the strongest significant prognosticator related to OS (hazard ratio 3.7 [95%CI 2.5-5.5], p < 0.001). No RLT-related deaths or treatment discontinuations occurred; the most frequent RLT-related Grade 3/4 adverse events were anemia (18/254 patients, 7.1%), thrombocytopenia (11/254, 4.3%), and lymphopenia (7/254, 2.8%). RLT-related xerostomia, all grade 1/2, was noted in 53/254 (20.9%)., Conclusions: In a large, prospectively observed "real-world" cohort with late-stage/end-stage mCRPC and conventional treatment failure,177 Lu-PSMA-617 RLT was effective, safe, and well-tolerated. Early biochemical disease control by such therapy was associated with better OS. Prospective study earlier in the disease course may be warranted., (© 2021. The Author(s).)- Published
- 2022
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39. Value of Combined PET Imaging with [ 18 F]FDG and [ 68 Ga]Ga-PSMA-11 in mCRPC Patients with Worsening Disease during [ 177 Lu]Lu-PSMA-617 RLT.
- Author
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Khreish F, Ribbat K, Bartholomä M, Maus S, Stemler T, Hierlmeier I, Linxweiler J, Schreckenberger M, Ezziddin S, and Rosar F
- Abstract
Despite the promising results of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) in metastatic castration-resistant prostate cancer (mCRPC), some patients show worsening disease during PSMA-RLT. We investigated the value of combined [
18 F]FDG and [68 Ga]Ga-PSMA-11 PET imaging in this setting. In n = 29 mCRPC patients with worsening disease after a median of four cycles of [177 Lu]Lu-PSMA-617 RLT, combined [18 F]FDG and [68 Ga]Ga-PSMA-11 PET imaging was performed to detect [18 F]FDG-avid lesions with low or no PSMA expression (mismatch lesions). To evaluate prognostic implication of mismatch, survival analyses regarding presence, location, and [18 F]FDG PET-derived parameters such as SUVmax , metabolic tumor volume (MTVm ), and total lesion glycolysis (TLGm ) of mismatch findings were performed. Seventeen patients (59%) showed at least one mismatch metastasis. From the time point of combined PET imaging, the median overall survival (OS) of patients with mismatch findings was significantly (p = 0.008) shorter than those without (3.3 vs. 6.1 mo). Patients with a high MTVm revealed a significantly ( p = 0.034) shorter OS of 2.6 mo than patients with low MTVm (5.3 mo). Furthermore, patients with hepatic mismatch showed a significantly ( p = 0.049) shorter OS than those without (2.9 vs. 5.3 mo). Difference in OS regarding SUVmax and TLGm was not significant. In mCRPC patients with worsening disease during PSMA-RLT, combined [18 F]FDG and [68 Ga]Ga-PSMA-11 PET imaging is essential to identify mismatch findings, as these are associated with poor outcomes requiring a change in therapy management.- Published
- 2021
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40. Response Assessment and Prediction of Progression-Free Survival by 68 Ga-PSMA-11 PET/CT Based on Tumor-to-Liver Ratio (TLR) in Patients with mCRPC Undergoing 177 Lu-PSMA-617 Radioligand Therapy.
- Author
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Khreish F, Wiessner M, Rosar F, Ghazal Z, Sabet A, Maus S, Linxweiler J, Bartholomä M, and Ezziddin S
- Subjects
- Aged, Aged, 80 and over, Biomarkers metabolism, Follow-Up Studies, Humans, Kaplan-Meier Estimate, Liver radiation effects, Male, Middle Aged, Molecular Imaging, Neoplasm Metastasis, Progression-Free Survival, Retrospective Studies, Treatment Outcome, Gallium Isotopes, Gallium Radioisotopes, Liver pathology, Lutetium, Prostate-Specific Antigen, Prostatic Neoplasms, Castration-Resistant radiotherapy, Radiopharmaceuticals, Radiotherapy methods
- Abstract
At present, little is known about the molecular imaging-based response assessment of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy with
177 Lutetium (177 Lu-PSMA-617 RLT) in metastatic castration-resistant prostate cancer (mCRPC). Our study evaluated the response to RLT using both molecular imaging and biochemical response assessments, and their potential prediction of progression-free survival (PFS). Fifty-one consecutive patients given two cycles of RLT at 6-week intervals were analyzed retrospectively.68 Ga-PSMA-11 PET/CT was obtained about 2 weeks prior to the first and 4-6 weeks after the second cycle. Molecular imaging-based response using SUVpeak and tumor-to-liver ratio (TLR) was determined by modified PERCIST criteria. ∆TLR and ∆SUV were significantly correlated with ∆PSA ( p < 0.001, each). After a median follow-up of 49 months, the median PFS (95% CI) was 8.0 (5.9-10.1) months. In univariate analysis, responders showing partial remission (PRPSA and PRTLR ) had significantly ( p < 0.001, each) longer PFS (median: 10.5 and 9.3 months) than non-responders showing either stable or progressive disease (median: 4.0 and 3.5 months). Response assessment using SUVpeak failed to predict survival. In multivariable analysis, response assessment using TLR was independently associated with PFS ( p < 0.001), as was good performance status ( p = 0.002). Molecular imaging-based response assessment with68 Ga-PSMA-11 PET/CT using normalization of the total lesion PSMA over healthy liver tissue uptake (TLR) could be an appropriate biomarker to monitor RLT in mCRPC patients and to predict progression-free survival (PFS) of this treatment modality.- Published
- 2021
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41. Renal Safety of [ 177 Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Compromised Baseline Kidney Function.
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Rosar F, Kochems N, Bartholomä M, Maus S, Stemler T, Linxweiler J, Khreish F, and Ezziddin S
- Abstract
Background: Radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) is an effective antitumor-treatment in metastatic castration-resistant prostate carcinoma (mCRPC). Concerns of potential nephrotoxicity are based on renal tubular PSMA expression and the resulting radiopharmaceutical retention during RLT, but data confirming clinically significant renal toxicity are still lacking. In this study, patients with significantly impaired baseline kidney function before initiation of therapy were investigated for treatment-associated nephrotoxicity and the potential relationship with administered activities of [
177 Lu]Lu-PSMA-617. Methods: Twenty-two mCRPC patients with impaired renal function (glomerular filtration rate (GFR) ≤ 60 mL/min) who received more than two cycles of [177 Lu]Lu-PSMA-617 RLT (median 5 cycles and median 6-week time interval between consecutive cycles) were analyzed in this study. Patients were treated within a prospective patient registry (REALITY Study, NCT04833517). Cumulative administered activities ranged from 17.1 to 85.6 GBq with a median activity of 6.5 GBq per cycle. Renal function was closely monitored during and after PSMA-RLT. Results: Mean pre-treatment GFR was 45.0 ± 10.7 mL/min. After two (22/22 patients), four (20/22 patients), and six cycles (10/22 patients) of RLT, a significant increase of GFR was noted (each p < 0.05). End-of-treatment GFR (54.1 ± 16.7 mL/min) was significantly higher than baseline GFR ( p = 0.016). Only one patient experienced deterioration of renal function (change of CTCAE grade 2 to 3). The remaining patients showed no significant reduction of GFR, including follow-up assessments (6, 9, and 12 months), and even showed improved (10/22 patients) or unchanged (11/22 patients) CTCAE-based renal impairment grades during and after the end of PSMA-RLT. No significant correlation between the change in GFR and per-cycle ( p = 0.605) or cumulative ( p = 0.132) administered activities were found. Conclusions: As pre-treatment chronic kidney failure did not lead to detectable RLT-induced deterioration of renal function in our study, the nephrotoxic potential of [177 Lu]Lu-PSMA-617 RLT may be overestimated and not of clinical priority in the setting of palliative treatment in mCRPC. We suggest not to categorically exclude patients from enrolment to PSMA-RLT due to renal impairment.- Published
- 2021
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42. Efficacy and Safety of [ 225 Ac]Ac-PSMA-617 Augmented [ 177 Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Highly Advanced mCRPC with Poor Prognosis.
- Author
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Rosar F, Krause J, Bartholomä M, Maus S, Stemler T, Hierlmeier I, Linxweiler J, Ezziddin S, and Khreish F
- Abstract
The use of
225 Ac in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), either as monotherapy or in combination with177 Lu, is a promising therapy approach in patients with metastatic castration-resistant prostate carcinoma (mCRPC). In this study, we report the efficacy and safety of [225 Ac]Ac-PSMA-617 augmented [177 Lu]Lu-PSMA-617 RLT in177 Lu-naive mCRPC patients ( n = 15) with poor prognosis (presence of visceral metastases, high total tumor burden with diffuse bone metastases or a short PSA doubling time of <2 months). Biochemical (by PSA serum value) and molecular imaging response (by [68 Ga]Ga-PSMA-11 PET/CT) was assessed after two cycles of [177 Lu]Lu-PSMA-617 RLT, with at least one [225 Ac]Ac-PSMA-617 augmentation. In addition, PSA-based progression-free survival (PSA-PFS), overall survival (OS) and toxicity (according to CTCAE) were analyzed. We observed a biochemical- and molecular imaging-based partial remission in 53.3% (8/15) and 66.7% (10/15) of patients, respectively. The median PSA-PFS and OS was 9.1 and 14.8 months, respectively. No serious acute adverse events were recorded. Two out of fifteen patients experienced grade 3 anemia. No other grade 3/4 toxicities were observed. RLT-related xerostomia (grade 1/2) was recorded in 2/15 patients. Our data showed a high clinical efficacy with a favorable side effects profile of [225 Ac]Ac-PSMA-617 augmented [177 Lu]Lu-PSMA-617 RLT in this highly challenging patient cohort.- Published
- 2021
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43. Comparison of different methods for post-therapeutic dosimetry in [ 177 Lu]Lu-PSMA-617 radioligand therapy.
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Rosar F, Schön N, Bohnenberger H, Bartholomä M, Stemler T, Maus S, Khreish F, Ezziddin S, and Schaefer-Schuler A
- Abstract
Background: Dosimetry is of high importance for optimization of patient-individual PSMA-targeted radioligand therapy (PSMA-RLT). The aim of our study was to evaluate and compare the feasibility of different approaches of image-based absorbed dose estimation in terms of accuracy and effort in clinical routine., Methods: Whole-body planar images and SPECT/CT images were acquired from 24 patients and 65 cycles at 24h, 48h, and ≥96h after administration of a mean activity of 6.4 GBq [
177 Lu]Lu-PSMA-617 (range 3-10.9 GBq). Dosimetry was performed by use of the following approaches: 2D planar-based dosimetry, 3D SPECT/CT-based dosimetry, and hybrid dosimetry combining 2D and 3D data. Absorbed doses were calculated according to IDAC 2.1 for the kidneys, the liver, the salivary glands, and bone metastases., Results: Mean absorbed doses estimated by 3D dosimetry (the reference method) were 0.54 ± 0.28 Gy/GBq for the kidneys, 0.10 ± 0.05 Gy/GBq for the liver, 0.81 ± 0.34 Gy/GBq for the parotid gland, 0.72 ± 0.39 Gy/GBq for the submandibular gland, and 1.68 ± 1.32 Gy/GBq for bone metastases. Absorbed doses of normal organs estimated by hybrid dosimetry showed small, non-significant differences (median up to 4.0%) to the results of 3D dosimetry. Using 2D dosimetry, in contrast, significant differences (median up to 10.9%) were observed. Regarding bone metastases, small, but significant differences (median up to 7.0%) of absorbed dose were found for both, 2D dosimetry and hybrid dosimetry. Bland-Altman analysis revealed high agreement between hybrid dosimetry and 3D dosimetry for normal organs and bone metastases, but substantial differences between 2D dosimetry and 3D dosimetry., Conclusion: Hybrid dosimetry provides high accuracy in estimation of absorbed dose in comparison to 3D dosimetry for all important organs and is therefore feasible for use in individualized PSMA-RLT.- Published
- 2021
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44. Molecular imaging and biochemical response assessment after a single cycle of [ 225 Ac]Ac-PSMA-617/[ 177 Lu]Lu-PSMA-617 tandem therapy in mCRPC patients who have progressed on [ 177 Lu]Lu-PSMA-617 monotherapy.
- Author
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Rosar F, Hau F, Bartholomä M, Maus S, Stemler T, Linxweiler J, Ezziddin S, and Khreish F
- Subjects
- Aged, Aged, 80 and over, Humans, Male, Middle Aged, Molecular Imaging methods, Positron Emission Tomography Computed Tomography methods, Retrospective Studies, Survival Analysis, Treatment Outcome, Dipeptides metabolism, Heterocyclic Compounds, 1-Ring metabolism, Prostate-Specific Antigen metabolism, Prostatic Neoplasms, Castration-Resistant metabolism, Prostatic Neoplasms, Castration-Resistant therapy, Radiopharmaceuticals therapeutic use
- Abstract
Rationale: Despite the promising results of prostate-specific membrane antigen (PSMA)-targeted
177 Lu radioligand therapy in metastatic castration-resistant prostate carcinoma (mCRPC), some patients do not respond and other patients with initially good response develop resistance to this treatment. In this study, we investigated molecular imaging and biochemical responses after a single cycle of [225 Ac]Ac-PSMA-617/[177 Lu]Lu-PSMA-617 tandem therapy in patients who had progressed on [177 Lu]Lu-PSMA-617 monotherapy. Methods: Seventeen patients with mCRPC were included in a retrospective, monocenter study. Molecular imaging-based response was assessed by modified PERCIST criteria using the whole-body total lesion PSMA (TLP) and molecular tumour volume (MTV) derived from [68 Ga]Ga-PSMA-11 PET/CT. Biochemical response was evaluated according to PCWG3 criteria using the prostate-specific antigen (PSA) serum value. Concordance and correlation statistics as well as survival analyses were performed. Results: Based on the molecular imaging-based response assessment, 5 (29.4%) patients showed partial remission and 7 (41.2%) had stable disease. The remaining 5 (29.4%) patients had further progression, four with an increase in TLP/MTV of >30% and one with stable TLP/MTV but appearance of new metastases. Based on the biochemical response assessment, 5 (29.4%), 8 (47.1%), and 4 (23.5%) patients showed partial remission, stable disease, and progressive disease, respectively. A comparison of the response assessment methods showed a concordance of 100% (17/17) between TLP and MTV and 70.6% (12/17) between TLP/MTV and PSA. Patients with partial remission, independently assessed by each method, had better overall survival (OS) than patients with either stable or progressive disease. The difference in OS was statistically significant for the molecular imaging response assessment (median OS not reached vs. 8.3 m, p = 0.044), but not for the biochemical response assessment (median OS 18.1 m vs. 9.4 m, p = 0.468). Conclusion: Based on both assessment methods, [225 Ac]Ac-PSMA-617/[177 Lu]Lu-PSMA-617 tandem therapy is an effective treatment for the highly challenging cohort of patients with mCRPC who have progressed on [177 Lu]Lu-PSMA-617 monotherapy. Molecular imaging response and biochemical PSA response were mostly concordant, though a considerable number of cases (29.4%) were discordant. Molecular imaging response reflecting the change in total viable tumour burden appears to be superior to PSA change in estimating survival outcome after tandem therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)- Published
- 2021
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45. Response and outcome of liver metastases in patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing 177 Lu-PSMA-617 radioligand therapy.
- Author
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Khreish F, Kochems N, Rosar F, Sabet A, Ries M, Maus S, Saar M, Bartholomä M, and Ezziddin S
- Subjects
- Dipeptides therapeutic use, Heterocyclic Compounds, 1-Ring therapeutic use, Humans, Male, Prostate-Specific Antigen, Retrospective Studies, Tomography, X-Ray Computed, Treatment Outcome, Liver Neoplasms radiotherapy, Liver Neoplasms secondary, Prostatic Neoplasms, Castration-Resistant pathology, Prostatic Neoplasms, Castration-Resistant radiotherapy
- Abstract
Purpose: Little is known about the efficacy of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) against liver metastases of metastatic castration-resistant prostate cancer (mCRPC). We retrospectively analyzed efficacy-related outcomes of
177 Lu-PSMA-617 RLT in this setting and potential predictors of those outcomes., Methods: Twenty-eight consecutive mCRPC patients with liver metastases given177 Lu-PSMA-617 RLT were analyzed retrospectively. Their planned regimen was 4-6 cycles at 6 ± 2-week intervals; the mean activity/cycle was 6.5 ± 0.5 GBq. Hepatic response was determined by modified positron emission tomography response criteria in solid tumors; association of such response with overall survival (OS) was tested, as were relationships of the selected patient, disease, and treatment characteristics with hepatic progression-free survival (PFShep ) and OS. Survival analyses used Kaplan-Meier curves, log-rank test at p < 0.05 significance, and Cox proportional-hazards modeling., Results: Median (minimum-maximum) follow-up was 37.5 (2.3-50.6) months. In liver metastases, complete or partial response was observed in 6 patients (21%) each, and stable disease in 1 (4%), for hepatic disease control in 46%. Overall, median (95% confidence interval) PFShep was 5.7 (2.2-9.2) months, and OS, 11.7 (3.0-20.4) months. Patients with hepatic disease control did not reach the median OS, while those with hepatic progressive disease had median OS (95% confidence interval) of 6.4 (1.6-11.1) months. In multivariate analysis, hepatic disease control by177 Lu-PSMA-617 RLT was significantly independently associated with OS, as was a prostate-specific antigen decline of ≥ 50% after 2 RLT cycles, and good baseline performance status (Eastern Cooperative Oncology Group 0-1). Hepatic tumor burden (≤ 25% vs. > 25% of liver volume) had no apparent relationship with hepatic tumor response, PFShep , or OS., Conclusion:177 Lu-PSMA-617 RLT frequently controlled liver metastases, resulting in long PFShep and significantly improved OS. Hepatic tumor burden appeared to lack any relationship with treatment efficacy, supporting177 Lu-PSMA-617 RLT of late-stage/end-stage mCRPC with liver metastases.- Published
- 2021
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46. Neuron-specific enolase has potential value as a biomarker for [ 18 F]FDG/[ 68 Ga]Ga-PSMA-11 PET mismatch findings in advanced mCRPC patients.
- Author
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Rosar F, Ribbat K, Ries M, Linxweiler J, Bartholomä M, Maus S, Schreckenberger M, Ezziddin S, and Khreish F
- Abstract
Background: PSMA-targeted radioligand therapy (PSMA-RLT) yielded impressive results in the metastasized castration-resistant prostate carcinoma (mCRPC) setting. High expression of PSMA is essential for successful PSMA-RLT. However, some patients develop [
18 F]FDG-avid lesions with low or no PSMA expression ([18 F]FDG/[68 Ga]Ga-PSMA-11 mismatch findings on PET/CT) in the course of treatment. Those lesions are not affected by PSMA-RLT and a change in therapy management is needed. To enable early mismatch detection, possible blood parameters as indicators for the occurrence of [18 F]FDG/[68 Ga]Ga-PSMA-11 mismatch findings on PET/CT were evaluated., Methods: Retrospective study of N = 66 advanced mCRPC patients with dual [68 Ga]Ga-PSMA-11 and [18 F]FDG PET/CT imaging within 4 weeks, who were referred for or received [177 Lu]Lu-PSMA-617 radioligand therapy. Prostate-specific antigen (PSA), neuron-specific enolase (NSE), gamma-glutamyltransferase (GGT), and alkaline phosphatase (ALP) were tested as indicators for the occurrence of [18 F]FDG/[68 Ga]Ga-PSMA-11 mismatch findings. Additional to absolute values, relative changes (ΔPSA, ΔNSE, ΔGGT, ΔALP) over a period of 4 ± 1 weeks prior to [18 F]FDG PET/CT were analyzed., Results: In total, 41/66 (62%) patients revealed at least one [18 F]FDG/[68 Ga]Ga-PSMA-11 mismatch finding on PET/CT. These mismatch findings were detected in 13/41 (32%) patients by screening for and in 28/41 (68%) patients during PSMA-RLT. NSE serum level (55.4 ± 44.6 μg/l vs. 18.5 ± 8 μg/l, p < 0.001) and ΔNSE (93.8 ± 124.5% vs. 2.9 ± 39.5%, p < 0.001) were significantly higher in the mismatch group than in the non-mismatch group. No significant differences were found for serum PSA (p = 0.424), ΔPSA (p = 0.417), serum ALP (p = 0.937), ΔALP (p = 0.611), serum GGT (p = 0.773), and ΔGGT (p = 0.971). For NSE and ΔNSE, the maximum value of the Youden index in ROC analysis was at a cut-off level of 26.8 μg/l (sensitivity 78%, specificity 96%) and at + 13.9% (sensitivity 84%, specificity 75%), respectively. An introduced scoring system of both parameters achieved a sensitivity of 90% and a specificity of 88% for the occurrence of [18 F]FDG/[68 Ga]Ga-PSMA-11 mismatch., Conclusion: We observed a significantly higher absolute serum concentration and a higher relative increase of NSE in advanced mCRPC patients with [18 F]FDG-avid and insufficient PSMA expressing metastases ([18 F]FDG/[68 Ga]Ga-PSMA-11 mismatch findings on PET/CT) in our cohort. NSE might be used as a potential laboratory indicator for [18 F]FDG/[68 Ga]Ga-PSMA-11 mismatch findings, if this observation is confirmed in future, ideally prospective, studies in larger patient cohorts.- Published
- 2020
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47. Results from extended lymphadenectomies with [ 111 In]PSMA-617 for intraoperative detection of PSMA-PET/CT-positive nodal metastatic prostate cancer.
- Author
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Jilg CA, Reichel K, Stoykow C, Rischke HC, Bartholomä M, Drendel V, von Büren M, Schultze-Seemann W, Meyer PT, and Mix M
- Abstract
Purpose: Identification of suspicious PSMA-PET/CT-positive lymph node (LN) metastases (LNM) from prostate cancer (PCa) during lymphadenectomy (LA) is challenging. We evaluated an
111 In-labelled PSMA ligand (DKFZ-617, referred to as [111 In]PSMA-617) as a γ-emitting tracer for intraoperative γ-probe application for resected tissue samples in PCa patients. Forty-eight hours prior to LA, [111 In]PSMA-617 was administered intravenously in 23 patients with suspected LNM on PSMA-PET/CT (n = 21 with biochemical relapse, n = 2 at primary therapy). Resected tissue samples (LN, LNM and fibrofatty tissue) were measured ex situ by a γ-probe expressed as counts per second (CPSnorm ). [111 In]PSMA-617 tissue sample uptake was measured by a germanium detector for verification and calculated as %IAlbm (percent injected activity per kilogram lean body mass at time of surgery). Based on a clinical requirement for a specificity > 95%, thresholds for both ex situ measurements were chosen accordingly. Correlation of the results from PET/CT, γ-probe and germanium detector with histopathology was done., Results: Eight hundred sixty-four LNs (197 LNM) were removed from 275 subregions in 23 patients, on average 8.6 ± 14.9 LNM per patient. One hundred four of 275 tissue samples showed cancer. Median γ-probe and germanium detector results were significantly different between tumour-affected (33.5 CPSnorm , 0.71 %IAlbm ) and tumour-free subregions (3.0 CPSnorm , 0.03 %IAlbm ) (each p value < 0.0001). For the chosen γ-probe cut-off (CPSnorm > 23) and germanium detector cut-off (%IAlbm > 0.27), 64 and 74 true-positive and 158 true-negative samples for both measurements were identified. Thirty-nine and 30 false-negative and 6 and 5 false-positive tissue samples were identified by γ-probe and germanium detector measurements., Conclusion: [111 In]PSMA-617 application for LA is feasible in terms of an intraoperative real-time measurement with a γ-probe for detection of tumour-affected tissue samples. γ-probe results can be confirmed by precise germanium detector measurements and were significantly different between tumour-affected and tumour-free samples.- Published
- 2020
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48. 225 Ac-PSMA-617/ 177 Lu-PSMA-617 tandem therapy of metastatic castration-resistant prostate cancer: pilot experience.
- Author
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Khreish F, Ebert N, Ries M, Maus S, Rosar F, Bohnenberger H, Stemler T, Saar M, Bartholomä M, and Ezziddin S
- Subjects
- Actinium, Dipeptides therapeutic use, Heterocyclic Compounds, 1-Ring therapeutic use, Humans, Male, Prostate-Specific Antigen, Radiopharmaceuticals, Retrospective Studies, Treatment Outcome, Prostatic Neoplasms, Castration-Resistant radiotherapy
- Abstract
Purpose: Up to 30% of patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) never respond or develop resistance to
177 Lu-labeled PSMA-targeted radioligand monotherapy. Single-agent PSMA-targeted radioligand therapy (PRLT) with the alpha-emitter225 Ac showed promise against mCRPC but may cause severe and/or persistent xerostomia, which may substantially impair patients' quality-of-life. We hypothesized that when177 Lu-PSMA ligand alone is ineffective, tandem therapy with low-activity225 Ac-PSMA ligand plus full activity of the beta emitter may enhance efficacy while minimizing xerostomia severity., Methods: We retrospectively analyzed pilot experience with 1 course of225 Ac-PSMA-617/177 Lu-PSMA-617 tandem therapy in our first 20 patients with mCRPC receiving this intervention after insufficiently responding to177 Lu-PSMA-617 monotherapy. This cohort had late-stage/end-stage disease with high baseline prostate-specific antigen (PSA) concentration (median 215 ng/mL), heavy pre-treatment (abiraterone and/or enzalutamide, and177 Lu-PRLT [median cumulative activity, 26.3 GBq] in 20/20 patients, 100%; docetaxel and/or cabazitaxel in 13/20 patients, 65%), and frequent Eastern Cooperative Oncology Group performance status of 2 (8/20 patients, 40%)., Results: Median (minimum-maximum) administered activities were225 Ac-PSMA-617, 5.3 (1.5-7.9) MBq, and177 Lu-PSMA-617, 6.9 (5.0-11.6) GBq. Significant responders to tandem therapy received177 Lu-PSMA-617 monotherapy as maintenance (median [minimum-maximum]: 1 [0-5] cycle). After a median (minimum-maximum) 22 (14-63) weeks' follow-up, 13/20 patients (65%) had as best biochemical response a PSA decline > 50%. Median (95% confidence interval) progression-free survival was 19 (12-26) weeks, and overall survival was 48 (4-92) weeks post-tandem therapy administration. Xerostomia was reported as grade 1 (very mild) in 8/20 patients (40%), grade 2 (mild) in 5/20 (25%), and grade 3/4 in 0/20., Conclusions: Our results suggest that a single course of tandem therapy with low-activity225 Ac-PSMA-617/full-activity177 Lu-PSMA-617 may safely enhance response to PRLT in men with late-stage/end-stage mCRPC while minimizing xerostomia severity. Formal study of this combination is warranted.- Published
- 2020
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49. New insights in the paradigm of upregulation of tumoral PSMA expression by androgen receptor blockade: Enzalutamide induces PSMA upregulation in castration-resistant prostate cancer even in patients having previously progressed on enzalutamide.
- Author
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Rosar F, Dewes S, Ries M, Schaefer A, Khreish F, Maus S, Bohnenberger H, Linxweiler J, Bartholomä M, Ohlmann C, and Ezziddin S
- Subjects
- Benzamides, Humans, Male, Nitriles, Phenylthiohydantoin, Positron Emission Tomography Computed Tomography, Prospective Studies, Receptors, Androgen, Up-Regulation, Prostatic Neoplasms, Castration-Resistant diagnostic imaging, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
Purpose: There is preliminary evidence for prostate-specific membrane antigen (PSMA) upregulation effects of androgen receptor blockade in prostate cancer. In an attempt to find the best condition for PSMA radioligand therapy in metastatic castration-resistant prostate cancer (mCRPC) patients, we evaluated the effect of oral enzalutamide in patients, predominantly having previously progressed on enzalutamide treatment., Methods: Ten patients with advanced mCRPC scheduled for PSMA radioligand therapy were examined with
68 Ga-PSMA-11 PET/CT before and after a mean of 11.8 days of enzalutamide 160 mg/day. Imaging results were compared using total PSMA tumor burden quantification. We assessed whole-body total lesion PSMA (TLP), defined as SUVmean × tumor volume and calculated TLP-to-liver ratio (TLP-LR), TLP-to-parotid gland ratio (TLP-PR), and TLP-to-kidney ratio (TLP-KR)., Results: The mean (median) increase of TLP-LR, TLP-PR, and TLP-KR in the cohort was 49.3% (38.8%), 45.1% (23.5%), and 54.9% (37.6%), respectively. These increases were statistically significant (p = 0.002, p = 0.014, and p = 0.014), while PSA values did not change significantly (p = 0.846). Seven of the 10 patients had previously undergone enzalutamide treatment with eventual progression, formally classified as treatment failure. No side effects were noted in the short term., Conclusions: Our results suggest that enzalutamide could be considered as a PSMA radioligand treatment enhancing primer medication, which may increase PSMA expression by a dimension of 50% in mCRPC. The effect was shown even in patients having previously failed enzalutamide treatment for arrest of progression in the mCRPC setting. Our observation deserves evaluation in a prospective setting.- Published
- 2020
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50. Combination treatment with hypofractionated radiotherapy plus IL-2/anti-IL-2 complexes and its theranostic evaluation.
- Author
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Jing H, Hettich M, Gaedicke S, Firat E, Bartholomä M, and Niedermann G
- Subjects
- Adoptive Transfer, Animals, B7-H1 Antigen genetics, B7-H1 Antigen metabolism, Biomarkers, Cell Line, Tumor, Combined Modality Therapy, Disease Models, Animal, Drug Synergism, Humans, Immunologic Factors pharmacology, Immunophenotyping, Killer Cells, Natural drug effects, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Mice, Neoplasms diagnostic imaging, Neoplasms etiology, Positron Emission Tomography Computed Tomography, Positron-Emission Tomography, Species Specificity, T-Lymphocyte Subsets drug effects, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Xenograft Model Antitumor Assays, Antibodies, Monoclonal pharmacology, Interleukin-2 pharmacology, Neoplasms pathology, Neoplasms therapy, Radiation Dose Hypofractionation
- Abstract
Background: Immunogenic radiotherapy (RT) can act synergistically with immune checkpoint blockers (ICBs). However, alternatives are needed for non-responding patients and those with pre-existing or ICB-induced autoimmune symptoms. Combination of RT with IL-2 could be an alternative. But IL-2 has a short half-life, and, by binding to its high-affinity receptor, it strongly stimulates immunosuppressive CD4+ Tregs and seems to promote potentially life-threatening vascular leakage. IL-2/anti-IL-2 complexes (IL-2c), which bind to the low-affinity receptor, have been reported to circumvent these disadvantages but they have not yet been thoroughly tested in conjunction with radiotherapy., Methods: We evaluated, in three mouse models, the antitumoral effects induced by hypofractionated RT (hRT) plus IL-2c. We also used non-invasive imaging with a newly developed PET tracer based on therapeutically active IL-2c and a PD-L1 PET tracer for the theranostic evaluation of the treatment and its side effects., Results: Treatment of mice bearing established B16 melanomas with hRT + IL-2c was superior to hRT + uncomplexed IL-2 or hRT alone; IL-2c alone was not effective. hRT + IL-2c was also synergistic in mice bearing C51 colon carcinomas or 4T1 mammary carcinomas. The better antitumor response correlated with increased tumor-specific CD8+ T cells and NK cells, but not CD4+ Tregs, in the irradiated tumor and in lymphoid organs. With the new PET tracer, we visualized the whole-body distribution of IL-2c and the bound receptors in naïve mice and tumor-bearing mice. Surprisingly, the tumor uptake was non-specific and only moderate. This prompted experiments demonstrating that specific IL-2c binding in the tumor is limited by IL-2 secreted by tumor-resident effector cells and that extratumorally expanded T and NK cells can infiltrate the irradiated tumor, which suggests that systemic immune activation considerably contributed to the reduction of tumor growth. Lastly, we show that a side effect of IL-2c treatment - a quite dramatic non-specific expansion of CD8+ T and NK cells - is only transient, and we visualized the associated splenomegaly as well as side effects on liver and lung by contrast-enhanced CT and PD-L1 PET., Conclusions: Our results show that the combination of immunogenic RT with IL-2c that are directed towards the low-affinity IL-2 receptor can be synergistic and more effective than the combination with uncomplexed IL-2. In addition, our theranostic evaluation provided insights into the mechanism of action and the side effects of IL-2c treatment.
- Published
- 2019
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