397 results on '"Buck AK"'
Search Results
52. Novel Structured Reporting Systems for Theranostic Radiotracers
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Lena Bundschuh, Rudolf A. Werner, Andreas K. Buck, Kenneth J. Pienta, Steven P. Rowe, Alexander Weich, Stefano Fanti, Martin G. Pomper, Michael A. Gorin, Mehrbod S. Javadi, Takahiro Higuchi, Constantin Lapa, Ken Herrmann, Ralph A. Bundschuh, and Werner RA, Bundschuh RA, Bundschuh L, Fanti S, Javadi MS, Higuchi T, Weich A, Pienta KJ, Buck AK, Pomper MG, Gorin MA, Herrmann K, Lapa C, Rowe SP.
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68Ga-DOTATOC ,medicine.medical_specialty ,Computer science ,Medizin ,Medical laboratory ,68Ga-DOTANOC ,somatostatin receptor ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Structured reporting ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Medical physics ,ddc:610 ,Radioactive Tracers ,Diagnostic Techniques and Procedures ,Neuroendocrine neoplasia ,Data abstraction ,Radiotherapy ,business.industry ,Positronen-Emissions-Tomografie ,68Ga-DOTATATE ,Reference Standards ,prostate cancer ,Variety (cybernetics) ,Clinical Practice ,Research Design ,030220 oncology & carcinogenesis ,business ,neuroendocrine neoplasia ,The State of the Art - Abstract
Standardized reporting is more and more routinely implemented in clinical practice and such structured reports have a major impact on a large variety of medical fields, e.g. laboratory medicine, pathology, and, recently, radiology. Notably, the field of nuclear medicine is constantly evolving, as novel radiotracers for numerous clinical applications are developed. Thus, framework systems for standardized reporting in this field may a) increase clinical acceptance of new radiotracers, b) allow for inter- and intra-center comparisons for quality assurance, and c) may be used in (global) multi-center studies to ensure comparable results and enable efficient data abstraction. In the last two years, several standardized framework systems for positron emission tomography (PET) radiotracers with potential theranostic applications have been proposed. These include systems for prostate-specific membrane antigen (PSMA)-targeted PET agents for the diagnosis and treatment of prostate cancer (PCa) and somatostatin receptor (SSTR)-targeted PET agents for the diagnosis and treatment of neuroendocrine neoplasias. In the present review, those standardized framework systems for PSMA- and SSTR-targeted PET will be briefly introduced followed by an overview of their advantages and limitations. In addition, potential applications will be defined, approaches to validate such concepts will be proposed, and future perspectives will be discussed.
- Published
- 2019
53. Impact of 11C-choline PET/CT on clinical decision making in recurrent prostate cancer: results from a retrospective two-centre trial
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Christina Bluemel, Christian Vollmer, Andreas K. Buck, Riccardo Schiavina, Stefano Fanti, Francesco Ceci, Renzo Mazzarotto, Sabine Droll, Paolo Castellucci, Tiziano Graziani, Eugenio Brunocilla, Ken Herrmann, Ceci F, Herrmann K, Castellucci P, Graziani T, Bluemel C, Schiavina R, Vollmer C, Droll S, Brunocilla E, Mazzarotto R, Buck AK, and Fanti S
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Androgen deprivation therapy ,C-11-Choline PET/CT ,Clinical impact ,Prostate cancer ,Biochemical relapse ,Salvage radiotherapy ,Multimodal Imaging ,Choline ,Clinical decision making ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Carbon Radioisotopes ,Aged ,Retrospective Studies ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Prostatic Neoplasms ,Retrospective cohort study ,General Medicine ,Middle Aged ,medicine.disease ,11c choline pet ct ,Positron emission tomography ,Predictive value of tests ,Positron-Emission Tomography ,Recurrent prostate cancer ,Radiopharmaceuticals ,business ,Tomography, X-Ray Computed - Abstract
PURPOSE: The aim of this retrospective two-centre study was to investigate the clinical impact of 11C-choline PET/CT on treatment management decisions in patients with recurrent prostate cancer (rPCa) after radical therapy. METHODS: Enrolled in this retrospective study were 150 patients (95 from Bologna, 55 from Würzburg) with rPCa and biochemical relapse (PSA mean ± SD 4.3 ± 5.5 ng/mL, range 0.2-39.4 ng/mL) after radical therapy. The intended treatment before PET/CT was salvage radiotherapy of the prostatic bed in 95 patients and palliative androgen deprivation therapy (ADT) in 55 patients. The effective clinical impact of 11C-choline PET/CT was rated as major (change in therapeutic approach), minor (same treatment, but modified therapeutic strategy) or none. Multivariate binary logistic regression analysis included PSA level, PSA kinetics, ongoing ADT, Gleason score, TNM, age and time to relapse. RESULTS: Changes in therapy after 11C-choline PET/CT were implemented in 70 of the 150 patients (46.7 %). A major clinical impact was observed in 27 patients (18 %) and a minor clinical impact in 43 (28.7 %). 11C-choline PET/CT was positive in 109 patients (72.7 %) detecting local relapse (prostate bed and/or iliac lymph nodes and/or pararectal lymph nodes) in 64 patients (42.7 %). Distant relapse (paraaortic and/or retroperitoneal lymph nodes and/or bone lesions) was seen in 31 patients (20.7 %), and both local and distant relapse in 14 (9.3 %). A significant difference was observed in PSA level and PSA kinetics between PET-positive and PET-negative patients (p 0.05). In both centres the same criteria to validate PET-positive findings were used: in 17.3 % of patients by histology and in 82.7 % of patients by correlative imaging and/or clinical follow-up (follow-up mean 20.5 months, median 18.3 months, range 6.2-60 months). CONCLUSION: 11C-Choline PET/CT had a significant impact on therapeutic management in rPCa patients. It led to an overall change in 46.7 % of patients, with a major clinical change implemented in 18 % of patients. Further prospective studies are needed to evaluate the effect of such treatment changes on patient survival.
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- 2014
54. Synthesis and preclinical evaluation of an Al(18)F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand
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Stefano Boschi, Michael Lassmann, Ken Herrmann, Roger Slavik, Claudio Spick, Johannes Czernin, Filippo Lodi, Stefano Fanti, Jason T. Lee, Liu Wei, Uta Eberlein, Andreas K. Buck, Gianfranco Cicoria, Seval Beykan, Boschi, S, Lee, Jt, Beykan, S, Slavik, R, Wei, L, Spick, C, Eberlein, U, Buck, Ak, Lodi, F, Cicoria, G, Czernin, J, Lassmann, M, Fanti, Stefano, and Herrmann, K.
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Glutamate Carboxypeptidase II ,Male ,Fluorine Radioisotopes ,Inbred C57BL ,urologic and male genital diseases ,Whole-Body Counting ,030218 nuclear medicine & medical imaging ,Mice ,0302 clinical medicine ,Glutamate carboxypeptidase II ,Tissue Distribution ,Gallium Isotopes ,Cancer ,Gamma counter ,Tumor ,Prostate cancer ,medicine.diagnostic_test ,Chemistry ,General Medicine ,Radiation Exposure ,Effective dose (pharmacology) ,Preclinical ,Surface ,Other Physical Sciences ,Nuclear Medicine & Medical Imaging ,Organ Specificity ,Positron emission tomography ,Isotope Labeling ,030220 oncology & carcinogenesis ,Biomedical Imaging ,Oligopeptides ,Biodistribution ,Metabolic Clearance Rate ,Clinical Sciences ,Gallium Radioisotopes ,Bioengineering ,Radiation Dosage ,Sensitivity and Specificity ,Cell Line ,03 medical and health sciences ,Dosimetry ,LNCaP ,Organometallic Compounds ,PSMA ,medicine ,Animals ,Radiology, Nuclear Medicine and imaging ,Antigens ,Edetic Acid ,business.industry ,F-18 ,Radiochemistry ,Prostatic Neoplasms ,Reproducibility of Results ,18F ,PET ,Positron-Emission Tomography ,Drug Evaluation ,Radiopharmaceuticals ,Nuclear medicine ,business ,Biomarkers ,Ex vivo - Abstract
PurposeThe aim of this study was to synthesize and preclinically evaluate an 18F-PSMA positron emission tomography (PET) tracer. Prostate-specific membrane antigen (PSMA) specificity, biodistribution, and dosimetry in healthy and tumor-bearing mice were determined.MethodsSeveral conditions for the labeling of 18F-PSMA-11 via 18F-AlF-complexation were screened to study the influence of reaction temperature, peptide amount, ethanol volume, and reaction time. After synthesis optimization, biodistribution and dosimetry studies were performed in C57BL6 mice. For proof of PSMA-specificity, mice were implanted with PSMA-negative (PC3) and PSMA-positive (LNCaP) tumors in contralateral flanks. Static and dynamic microPET/computed tomography (CT) imaging was performed.ResultsQuantitative labeling yields could be achieved with >97% radiochemical purity. The 18F-PSMA-11 uptake was more than 24-fold higher in PSMA-high LNCaP than in PSMA-low PC3 tumors (18.4 ± 3.3 %ID/g and 0.795 ± 0.260 %ID/g, respectively; p
55. Predictive value of C-X-C motif chemokine receptor 4-directed molecular imaging in patients with advanced adrenocortical carcinoma.
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Schloetelburg W, Hartrampf PE, Kosmala A, Serfling SE, Dreher N, Schirbel A, Fassnacht M, Buck AK, Werner RA, and Hahner S
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- Humans, Male, Female, Middle Aged, Aged, Adult, Peptides, Cyclic, Coordination Complexes, Predictive Value of Tests, Prognosis, Receptors, CXCR4 metabolism, Adrenocortical Carcinoma diagnostic imaging, Adrenocortical Carcinoma metabolism, Adrenocortical Carcinoma pathology, Positron Emission Tomography Computed Tomography, Adrenal Cortex Neoplasms diagnostic imaging, Adrenal Cortex Neoplasms pathology, Adrenal Cortex Neoplasms metabolism
- Abstract
Background: In patients affected with adrenocortical carcinoma (ACC), C-X-C motif chemokine receptor 4 (CXCR4) is highly expressed in sites of disease in an ex-vivo setting. We aimed to determine the predictive value of CXCR4-targeting [
68 Ga]Ga-PentixaFor PET/CT for outcome when compared to clinical parameters., Methods: We identified 41 metastasized ACC patients imaged with [68 Ga]Ga-PentixaFor PET/CT. Scans were assessed visually and on a quantitative level by manually segmenting the tumor burden (providing tumor volume [TV], peak/mean/maximum standardized uptake values [SUV] and tumor chemokine receptor binding on the cell surface [TRB], defined as SUVmean multiplied by tumor volume). Clinical parameters included sex, previous therapies, age, Weiss-Score, and Ki67 index. Following imaging, overall survival (OS) was recorded., Results: After [68 Ga]Ga-PentixaFor PET/CT, median OS was 9 months (range, 1-96 months). On univariable analysis, only higher TRB (per 10 ml, HR 1.004, 95%CI: 1.0001-1.007, P = 0.005) and presence of CXCR4-positive peritoneal metastases (PM) were associated with shorter OS (HR 2.03, 95%CI: 1.03-4.02, P = 0.04). Presence of CXCR4-positive liver metastases (LM) trended towards significance (HR 1.85, 0.9-4.1, P = 0.11), while all other parameters failed to predict survival. On multivariable analysis, only TRB was an independent predictor for OS (HR 1.0, 95%CI: 1.00-1.001, P = 0.02). On Kaplan-Meier analysis, TRB above median (13.3 months vs. below median, 6.4 months) and presence of CXCR4-positive PM (6.4 months, vs. no PM, 11.4 months) were associated with shorter survival (P < 0.05, respectively). Presence of LM, however, was also linked to less favorable outcome (8.5 months vs. no LM, 18.1 months), without reaching significance (P = 0.07)., Conclusions: In advanced ACC, elevated tumor chemokine receptor binding on the tumor cell surface detected through [68 Ga]Ga-PentixaFor PET/CT is an independent predictor for OS, while other imaging and clinical parameters failed to provide relevant prognostic information., (© 2024. The Author(s).)- Published
- 2024
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56. Interobserver Agreement Rates on CXCR4-Directed PET/CT in Patients with Marginal Zone Lymphoma.
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Werner RA, Zhi Y, Dreher N, Samnick S, Kosmala A, Higuchi T, Bundschuh L, Lapa C, Buck AK, Topp MS, Einsele H, Duell J, Serfling SE, and Bundschuh RA
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- Humans, Male, Female, Middle Aged, Aged, Adult, Aged, 80 and over, Receptors, CXCR4 metabolism, Lymphoma, B-Cell, Marginal Zone diagnostic imaging, Lymphoma, B-Cell, Marginal Zone pathology, Observer Variation, Positron Emission Tomography Computed Tomography methods
- Abstract
C-X-C motif chemokine receptor 4 (CXCR4)-directed molecular imaging provides excellent read-out capabilities in patients with marginal zone lymphoma (MZL). We aimed to determine the interobserver agreement rate of CXCR4-targeted PET/CT among readers with different levels of experience., Methods: 50 subjects with MZL underwent CXCR4-targeted PET/CT, which were reviewed by four readers (including two experienced and two less experienced observers). The following 8 parameters were investigated: overall scan result, CXCR4 density in lymphoma tissue, extranodal organ involvement, No. of affected extranodal organs and extranodal organ metastases, lymph node (LN) involvement and No. of affected LN areas and LN metastases. We applied intraclass correlation coefficients (ICC; < 0.4, poor; 0.4-0.59, fair; 0.6-0.74, good and > 0.74 excellent agreement rates)., Results: Among all readers, fair agreement was recorded for No. of affected extranodal organs (ICC, 0.40; 95% confidence interval [CI], 0.25-0.68), overall scan result (ICC, 0.42; 95%CI, 0.28-0.57), CXCR4 density in lymphoma tissue (ICC, 0.52; 95%CI, 0.38-0.66), and No. of extranodal organ metastases (ICC, 0.55; 95%CI, 0.41-0.61) and LN involvement (ICC, 0.59; 95%CI, 0.46-0.71). Good agreement rates were observed for No. of LN metastases (ICC, 0.71; 95%CI, 0.60-0.81) and No. of LN areas (ICC, 0.73; 95%CI, 0.63-0.82), while extranodal organ involvement (ICC, 0.35; 95%CI, 0.21-0.51) achieved poor concordance. On a reader-by-reader comparison, the experienced readers achieved significantly higher agreement rates in 4/8 (50%) investigated scan items (ICC, range, 0.21-0.90, P < / = 0.04). In the remaining 4/8 (50%), a similar trend with higher ICCs for the experienced readers was recorded (n.s.)., Conclusion: CXCR4-directed PET/CT mainly provided fair to good agreement rates for scan assessment, while a relevant level of experience seems to be required for an accurate imaging read-out., (© 2024. The Author(s).)
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- 2024
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57. DNA Damage and Repair in PBMCs after Internal Ex Vivo Irradiation with [ 223 Ra]RaCl 2 and [ 177 Lu]LuCl 3 Mixtures.
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Strobel I, Schumann S, Müller J, Buck AK, Port M, Lassmann M, Eberlein U, and Scherthan H
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- Humans, Male, Adult, DNA Breaks, Double-Stranded radiation effects, Radioisotopes, Lutetium, Female, Histones metabolism, Leukocytes, Mononuclear radiation effects, Leukocytes, Mononuclear metabolism, DNA Repair radiation effects, DNA Damage radiation effects
- Abstract
The combination of high and low LET radionuclides has been tested in several patient studies to improve treatment response. Radionuclide mixtures can also be released in nuclear power plant accidents or nuclear bomb deployment. This study investigated the DNA damage response and DNA double-strand break (DSB) repair in peripheral blood mononuclear cells (PBMCs) after internal exposure of blood samples of 10 healthy volunteers to either no radiation (baseline) or different radionuclide mixtures of the α- and β-emitters [
223 Ra]RaCl2 and [177 Lu]LuCl3 , i.e., 25 mGy/75 mGy, 50 mGy/50 mGy and 75 mGy/25 mGy, respectively. DSB foci and γ-H2AX α-track enumeration directly after 1 h of exposure or after 4 h or 24 h of repair revealed that radiation-induced foci (RIF) and α-track induction in 100 cells was similar for mixed α/β and pure internal α- or β-irradiation, as were the repair rates for all radiation qualities. In contrast, the fraction of unrepaired RIF (Qβ ) in PBMCs after mixed α/β-irradiation (50%223 Ra & 50%177 Lu: Qβ = 0.23 ± 0.10) was significantly elevated relative to pure β-irradiation (50 mGy: Qβ, pure = 0.06 ± 0.02), with a similar trend being noted for all mixtures. This α-dose-dependent increase in persistent foci likely relates to the formation of complex DNA damage that remains difficult to repair.- Published
- 2024
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58. Cranioencephalic functional lymphoid units in glioblastoma.
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Dobersalske C, Rauschenbach L, Hua Y, Berliner C, Steinbach A, Grüneboom A, Kokkaliaris KD, Heiland DH, Berger P, Langer S, Tan CL, Stenzel M, Landolsi S, Weber F, Darkwah Oppong M, Werner RA, Gull H, Schröder T, Linsenmann T, Buck AK, Gunzer M, Stuschke M, Keyvani K, Forsting M, Glas M, Kipnis J, Steindler DA, Reinhardt HC, Green EW, Platten M, Tasdogan A, Herrmann K, Rambow F, Cima I, Sure U, and Scheffler B
- Abstract
The ecosystem of brain tumors is considered immunosuppressed, but our current knowledge may be incomplete. Here we analyzed clinical cell and tissue specimens derived from patients presenting with glioblastoma or nonmalignant intracranial disease to report that the cranial bone (CB) marrow, in juxtaposition to treatment-naive glioblastoma tumors, harbors active lymphoid populations at the time of initial diagnosis. Clinical and anatomical imaging, single-cell molecular and immune cell profiling and quantification of tumor reactivity identified CD8
+ T cell clonotypes in the CB that were also found in the tumor. These were characterized by acute and durable antitumor response rooted in the entire T cell developmental spectrum. In contrast to distal bone marrow, the CB niche proximal to the tumor showed increased frequencies of tumor-reactive CD8+ effector types expressing the lymphoid egress marker S1PR1. In line with this, cranial enhancement of CXCR4 radiolabel may serve as a surrogate marker indicating focal association with improved progression-free survival. The data of this study advocate preservation and further exploitation of these cranioencephalic units for the clinical care of glioblastoma., (© 2024. The Author(s).)- Published
- 2024
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59. Prognostic role of quantitative [18F]FDG PET/CT parameters in adrenocortical carcinoma.
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Schlötelburg W, Hartrampf PE, Kosmala A, Fuss CT, Serfling SE, Buck AK, Schirbel A, Kircher S, Hahner S, Werner RA, and Fassnacht M
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- Humans, Male, Female, Middle Aged, Prognosis, Retrospective Studies, Adult, Aged, Radiopharmaceuticals, Young Adult, Fluorodeoxyglucose F18, Positron Emission Tomography Computed Tomography methods, Adrenocortical Carcinoma diagnostic imaging, Adrenocortical Carcinoma pathology, Adrenocortical Carcinoma mortality, Adrenal Cortex Neoplasms diagnostic imaging, Adrenal Cortex Neoplasms pathology, Adrenal Cortex Neoplasms mortality
- Abstract
Purpose: We aimed to evaluate the prognostic potential of baseline [
18 F]FDG PET/CT for overall survival (OS) in patients with adrenocortical carcinoma (ACC)., Methods: We performed a retrospective analysis of 67 treatment-naïve ACC patients with available [18 F]FDG PET/CT at time of initial diagnosis. Pretherapeutic PETs of primary tumors were manually segmented and quantitative parameters (maximum/mean/peak standardized uptake value (SUVmax/mean/peak ), metabolic tumor volume (MTV) and tumor lesion glycolysis (TLG, defined as TV*SUVmean ) were derived. Based on a visual read, absence (M0) or presence of metastatic disease (M1) were evaluated. Kaplan-Meier and Cox regression analyses were used to determine the prognostic value of the above mentioned markers on overall survival adjusted for established prognostic markers., Results: 24/67 patients (36%) presented with M0 based on PET/CT, while the remaining 43/67 (64%) had M1-status. 32/67 patients died during follow-up and median OS was 48 months. In 12% of patients FDG-PET detected additional metastatic lesion not clearly visible by CT only. In univariable analysis, all quantitatively derived PET parameters failed to reach significance (P ≥ 0.1), and only PET/CT-based M1-status and Ki-67 were associated with increased mortality (M1: HR 13.89, 95% CI 4.15-86.32, P < 0.001; Ki-67 HR 1.29, 95% CI 1.16-1.42; P < 0.0001). Using multivariable Cox regression analyses, M1-status (HR 9.69, 95% CI 2.82-60.99) and Ki-67 index (HR 1.29, 95% CI 1.13-1.04; P < 0.05) remained significant associated with OS., Conclusion: In treatment-naïve ACC patients, the quantitative PET parameter failed to predict OS, but presence of metastases detected by [18 F]FDG PET/CT and Ki-67 index were independently associated with shorter OS. Therefore, a simple visual PET-based read-out is of prognostic value at initial diagnosis, while time-consuming PET-based quantification can be omitted., (© 2024. The Author(s).)- Published
- 2024
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60. Modelling the In Vivo and Ex Vivo DNA Damage Response after Internal Irradiation of Blood from Patients with Thyroid Cancer.
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Schumann S, Scherthan H, Hartrampf PE, Göring L, Buck AK, Port M, Lassmann M, and Eberlein U
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- Humans, Middle Aged, Male, Female, Adult, Aged, DNA Damage, Iodine Radioisotopes therapeutic use, Tumor Suppressor p53-Binding Protein 1 metabolism, Histones metabolism, Leukocytes, Mononuclear metabolism, Leukocytes, Mononuclear radiation effects, Models, Biological, Thyroid Neoplasms radiotherapy, Thyroid Neoplasms blood, Thyroid Neoplasms pathology, Thyroid Neoplasms genetics, DNA Repair, DNA Breaks, Double-Stranded radiation effects
- Abstract
This work reports on a model that describes patient-specific absorbed dose-dependent DNA damage response in peripheral blood mononuclear cells of thyroid cancer patients during radioiodine therapy and compares the results with the ex vivo DNA damage response in these patients. Blood samples of 18 patients (nine time points up to 168 h post-administration) were analyzed for radiation-induced γ-H2AX + 53BP1 DNA double-strand break foci (RIF). A linear one-compartment model described the absorbed dose-dependent time course of RIF (Parameters: c characterizes DSB damage induction; k
1 and k2 are rate constants describing fast and slow repair). The rate constants were compared to ex vivo repair rates. A total of 14 patient datasets could be analyzed; c ranged from 0.012 to 0.109 mGy-1 , k2 from 0 to 0.04 h-1 . On average, 96% of the damage is repaired quickly with k1 (range: 0.19-3.03 h-1 ). Two patient subgroups were distinguished by k1 -values ( n = 6, k1 > 1.1 h-1 ; n = 8, k1 < 0.6 h-1 ). A weak correlation with patient age was observed. While induction of RIF was similar among ex vivo and in vivo, the respective repair rates failed to correlate. The lack of correlation between in vivo and ex vivo repair rates and the applicability of the model to other therapies will be addressed in further studies.- Published
- 2024
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61. [ 18 F]FDG PET/CT can trigger relevant oncological management changes leading to favorable outcome in iodine-negative thyroid cancer patients.
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Zhi Y, Higuchi T, Hackenberg S, Hagen R, Stöth M, Scherzad A, Buck AK, Werner RA, and Serfling SE
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- Humans, Female, Male, Middle Aged, Aged, Adult, Treatment Outcome, Radiopharmaceuticals, Thyroid Neoplasms diagnostic imaging, Thyroid Neoplasms therapy, Thyroid Neoplasms radiotherapy, Fluorodeoxyglucose F18, Positron Emission Tomography Computed Tomography methods, Iodine Radioisotopes therapeutic use
- Abstract
Background: In patients with iodine-negative thyroid cancer (TC), current guidelines endorse an [
18 F]FDG PET/CT to identify dedifferentiated sites of disease. We aimed to determine the rate of oncological management changes triggered by such a molecular imaging approach, along with the impact on outcome., Methods: 42 consecutive patients with negative findings on [131 I] whole body scan were scheduled for [18 F]FDG PET/CT and treatment based on PET results were initiated. To determine the impact on oncological management, we compared the therapeutic plan prior to and after molecular imaging. Based on imaging follow-up, the rate of controlled disease (CD, defined as stable disease, complete or partial response) was also recorded, thereby allowing to assess whether [18 F]FDG-triggered management changes can also lead to favorable outcome., Results: We observed no alterations of the treatment plan in 9/42 (21.4%) subjects (active surveillance in 9/9 [100%]). Oncological management was changed in the remaining 33/42 (78.6%; systemic treatment in 9/33 [27.3%] and non-systemic treatment in 24/33 [72.7%]). Among patients receiving non-systemic therapy, the following changes were noted: surgery in 20/24 (83.3%) and radiation therapy in 4/24 (16.7%). In the systemic group, tyrosine kinase inhibitor (TKI) was prescribed in 8/9 (88.9%), while radioiodine therapy based on a TKI-mediated redifferentiation approach was conducted in 1/9 (11.1%). In 26 subjects with available follow-up, rate of CD was 22/26 (84.6%) and among those, 15/22 (68.1%) had experienced previous management changes based on PET/CT findings., Conclusions: In subjects with iodine-negative TC, [18 F]FDG PET/CT triggered relevant management changes along with disease control in the vast majority of patients. As such, in dedifferentiated TC, [18 F]FDG PET/CT may serve as a relevant management tool and therapeutic decision-aid in the clinic., (© 2023. The Author(s).)- Published
- 2024
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62. PSMA-PET improves deep learning-based automated CT kidney segmentation.
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Leube J, Horn M, Hartrampf PE, Buck AK, Lassmann M, and Tran-Gia J
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- Humans, Radiopharmaceuticals, Male, Antigens, Surface, Glutamate Carboxypeptidase II, Deep Learning, Kidney diagnostic imaging, Positron Emission Tomography Computed Tomography methods
- Abstract
For dosimetry of radiopharmaceutical therapies, it is essential to determine the volume of relevant structures exposed to therapeutic radiation. For many radiopharmaceuticals, the kidneys represent an important organ-at-risk. To reduce the time required for kidney segmentation, which is often still performed manually, numerous approaches have been presented in recent years to apply deep learning-based methods for CT-based automated segmentation. While the automatic segmentation methods presented so far have been based solely on CT information, the aim of this work is to examine the added value of incorporating PSMA-PET data in the automatic kidney segmentation., Methods: A total of 108 PET/CT examinations (53 [
68 Ga]Ga-PSMA-I&T and 55 [18 F]F-PSMA-1007 examinations) were grouped to create a reference data set of manual segmentations of the kidney. These segmentations were performed by a human examiner. For each subject, two segmentations were carried out: one CT-based (detailed) segmentation and one PET-based (coarser) segmentation. Five different u-net based approaches were applied to the data set to perform an automated segmentation of the kidney: CT images only, PET images only (coarse segmentation), a combination of CT and PET images, a combination of CT images and a PET-based coarse mask, and a CT image, which had been pre-segmented using a PET-based coarse mask. A quantitative assessment of these approaches was performed based on a test data set of 20 patients, including Dice score, volume deviation and average Hausdorff distance between automated and manual segmentations. Additionally, a visual evaluation of automated segmentations for 100 additional (i.e., exclusively automatically segmented) patients was performed by a nuclear physician., Results: Out of all approaches, the best results were achieved by using CT images which had been pre-segmented using a PET-based coarse mask as input. In addition, this method performed significantly better than the segmentation based solely on CT, which was supported by the visual examination of the additional segmentations. In 80% of the cases, the segmentations created by exploiting the PET-based pre-segmentation were preferred by the nuclear physician., Conclusion: This study shows that deep-learning based kidney segmentation can be significantly improved through the addition of a PET-based pre-segmentation. The presented method was shown to be especially beneficial for kidneys with cysts or kidneys that are closely adjacent to other organs such as the spleen, liver or pancreas. In the future, this could lead to a considerable reduction in the time required for dosimetry calculations as well as an improvement in the results., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Michael Lassmann has received institutional grants by IPSEN Pharma, Nordic Nanovector, and Novartis. No other potential conflicts of interest relevant to this article exist., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)- Published
- 2024
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63. 4-Amidophenol Quinone Methide Precursors: Effective and Broad-Scope Nonoxime Reactivators of Organophosphorus-Inhibited Cholinesterases and Resurrectors of Organophosphorus-Aged Acetylcholinesterase.
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Lovins AR, Miller KA, Buck AK, Ensey DS, Homoelle RK, Murtha MC, Ward NA, Shanahan LA, Gutti G, Shriwas P, McElroy CA, Callam CS, and Hadad CM
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- Animals, Humans, Mice, Indolequinones pharmacology, Cholinesterase Inhibitors pharmacology, Acetylcholinesterase metabolism, Acetylcholinesterase drug effects, Butyrylcholinesterase metabolism, Organophosphorus Compounds pharmacology, Cholinesterase Reactivators pharmacology, Cholinesterase Reactivators chemistry
- Abstract
Acetylcholinesterase (AChE) inhibition by organophosphorus (OP) compounds poses a serious health risk to humans. While many therapeutics have been tested for treatment after OP exposure, there is still a need for efficient reactivation against all kinds of OP compounds, and current oxime therapeutics have poor blood-brain barrier penetration into the central nervous system, while offering no recovery in activity from the OP-aged forms of AChE. Herein, we report a novel library of 4-amidophenol quinone methide precursors (QMP) that provide effective reactivation against multiple OP-inhibited forms of AChE in addition to resurrecting the aged form of AChE after exposure to a pesticide or some phosphoramidates. Furthermore, these QMP compounds also reactivate OP-inhibited butyrylcholinesterase (BChE) which is an in vivo , endogenous scavenger of OP compounds. The in vitro efficacies of these QMP compounds were tested for reactivation and resurrection of soluble forms of human AChE and BChE and for reactivation of cholinesterases within human blood as well as blood and brain samples from a humanized mouse model. We identify compound 10c as a lead candidate due to its broad-scope efficacy against multiple OP compounds as well as both cholinesterases. With methylphosphonates, compound 10c (250 μM, 1 h) shows >60% recovered activity from OEt-inhibited AChE in human blood as well as mouse blood and brain, thus highlighting its potential for future in vivo analysis. For 10c , the effective concentration (EC
50 ) is less than 25 μM for reactivation of three different methylphosphonate-inhibited forms of AChE, with a maximum reactivation yield above 80%. Similarly, for OP-inhibited BChE, 10c has EC50 values that are less than 150 μM for two different methylphosphonate compounds. Furthermore, an in vitro kinetic analysis show that 10c has a 2.2- and 92.1-fold superior reactivation efficiency against OEt-inhibited and Oi Bu-inhibited AChE, respectively, when compared to an oxime control. In addition to 10c being a potent reactivator of AChE and BChE, we also show that 10c is capable of resurrecting (ethyl paraoxon)-aged AChE, which is another current limitation of oximes.- Published
- 2024
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64. Treatment of Organophosphorus Poisoning with 6-Alkoxypyridin-3-ol Quinone Methide Precursors: Resurrection of Methylphosphonate-Aged Acetylcholinesterase.
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Clay WK, Buck AK, He Y, Hernández Sánchez DN, Ward NA, Lear JM, Nguyen KQ, Clark BH, Sapia RJ, Lalisse RF, Sriraman A, Cadieux CL, McElroy CA, Callam CS, and Hadad CM
- Subjects
- Humans, Aged, Acetylcholinesterase metabolism, Cholinesterase Inhibitors chemistry, Molecular Docking Simulation, Organophosphorus Compounds pharmacology, Organophosphorus Compounds metabolism, Serine, Oximes, Soman, Organophosphate Poisoning, Cholinesterase Reactivators chemistry, Indolequinones
- Abstract
Organophosphorus (OP) nerve agents inhibit acetylcholinesterase (AChE), creating a cholinergic crisis in which death can occur. The phosphylated serine residue spontaneously dealkylates to the OP-aged form, which current therapeutics cannot reverse. Soman's aging half-life is 4.2 min, so immediate recovery (resurrection) of OP-aged AChE is needed. In 2018, we showed pyridin-3-ol-based quinone methide precursors (QMPs) can resurrect OP-aged electric eel AChE in vitro , achieving 2% resurrection after 24 h of incubation (pH 7, 4 mM). We prepared 50 unique 6-alkoxypyridin-3-ol QMPs with 10 alkoxy groups and five amine leaving groups to improve AChE resurrection. These compounds are predicted in silico to cross the blood-brain barrier and treat AChE in the central nervous system. This library resurrected 7.9% activity of OP-aged recombinant human AChE after 24 h at 250 μM, a 4-fold increase from our 2018 report. The best QMP ( 1b ), with a 6-methoxypyridin-3-ol core and a diethylamine leaving group, recovered 20.8% (1 mM), 34% (4 mM), and 42.5% (predicted maximum) of methylphosphonate-aged AChE activity over 24 h. Seven QMPs recovered activity from AChE aged with Soman and a VX degradation product (EA-2192). We hypothesize that QMPs form the quinone methide (QM) to realkylate the phosphylated serine residue as the first step of resurrection. We calculated thermodynamic energetics for QM formation, but there was no trend with the experimental biochemical data. Molecular docking studies revealed that QMP binding to OP-aged AChE is not the determining factor for the observed biochemical trends; thus, QM formation may be enzyme-mediated.
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- 2024
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65. Volumetric Parameters Derived from CXCR4-Directed PET/CT Predict Outcome in Patients with Gastrointestinal Neuroendocrine Carcinomas.
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Michalski K, Schlötelburg W, Hartrampf P, Heinrich M, Serfling S, Buck AK, Werner RA, Kosmala A, and Weich A
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- Humans, Positron Emission Tomography Computed Tomography, Retrospective Studies, Receptors, CXCR4, Gastrointestinal Neoplasms, Carcinoma, Neuroendocrine, Neuroendocrine Tumors pathology
- Abstract
Background: Gastro-entero-pancreatic neuroendocrine carcinomas (GEP-NECs) are an aggressive subgroup of neuroendocrine neoplasms (NENs). In patients affected with NEN, there is a growing body of evidence that increased C-X-C motif chemokine receptor (CXCR4) expression is linked to decreasing overall survival (OS) in an ex-vivo setting. Thus, we aimed to determine whether the in-vivo-derived CXCR4-directed whole-body PET signal can also determine GEP-NEC patients with shorter OS., Methods: We retrospectively included 16 patients with histologically proven GEP-NEC, who underwent CXCR4-directed PET/CT for staging and therapy planning. We assessed maximum, peak, and mean standardized uptake values as well as whole-body tumor volume (TV) and total-lesion uptake (TLU = SUVmean × TV) using a semi-automatic segmentation tool with a 50% threshold. Association of PET-based biomarkers and OS or radiographic progression-free survival (rPFS; according to RECIST 1.1 criteria) was analyzed using univariable and multivariable cox regression., Results: Median OS and rPFS was 7.5 and 7 months, respectively. A significant correlation between TV and TLU was found for OS (TV: hazard ratio (HR) 1.007 95% confidence interval (CI) 1.000-1.014, p = 0.0309; TLU: HR 1.002 95% CI 1.000-1.003, p = 0.0350) and rPFS (TV: HR 1.010 95% CI 1.002-1.021; p = 0.0275; TLU: HR 1.002 95% CI 1.000-1.004, p = 0.0329), respectively. No significant correlation with OS or rPFS was found for non-volumetric parameters (p > 0.4). TV remained a significant predictive marker for OS and rPFS in multivariable analysis (OS: HR 1.012 95%, CI 1.003-1.022, p = 0.0084; rPFS: HR 1.009, 95% CI 0.9999-1.019, p = 0.0491), whereas TLU remained only prognostic for OS (HR 1.009, 95% CI 0.9999-1.019, p = 0.0194) but narrowly failed significance for rPFS (p = 0.0559)., Conclusion: In-vivo assessment of CXCR4 PET-derived volumetric parameters is predictive for outcome of patients with GEP-NEC and could be used as a risk stratification tool, which detects patients prone to early progression., (© 2024. The Author(s).)
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- 2024
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66. CXCR4-directed PET/CT with [ 68 Ga]Ga-pentixafor in solid tumors-a comprehensive analysis of imaging findings and comparison with histopathology.
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Dreher N, Hahner S, Fuß CT, Schlötelburg W, Hartrampf PE, Serfling SE, Schirbel A, Samnick S, Higuchi T, Weich A, Lapa C, Rosenwald A, Buck AK, Kircher S, and Werner RA
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- Humans, Positron Emission Tomography Computed Tomography methods, Peptides, Cyclic, Gallium Radioisotopes, Receptors, CXCR4 metabolism, Neoplasms diagnostic imaging, Coordination Complexes
- Abstract
Background: C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in various solid cancers and can be targeted by CXCR4-directed molecular imaging. We aimed to characterize the in-vivo CXCR4 expression in patients affected with solid tumors, along with a comparison to ex-vivo findings., Methods: A total 142 patients with 23 different histologically proven solid tumors were imaged with CXCR4-directed PET/CT using [
68 Ga]Ga-pentixafor (total number of scans, 152). A semi-quantitative analysis of the CXCR4-positive tumor burden including maximum standardized uptake values (SUVmax ) and target-to-background ratios (TBR) using blood pool was conducted. In addition, we performed histopathological staining to determine the immuno-reactive score (IRS) from patients' tumor tissue and investigated possible correlations with SUVmax (by providing Spearman's rho ρ). Based on imaging, we also assessed the eligibility for CXCR4-targeted radioligand therapy or non-radioactive CXCR4 inhibitory treatment (defined as more than five CXCR4-avid target lesions [TL] with SUVmax above 10)., Results: One hundred three of 152 (67.8%) scans showed discernible uptake above blood pool (TBR > 1) in 462 lesions (52 primary tumors and 410 metastases). Median TBR was 4.4 (1.05-24.98), thereby indicating high image contrast. The highest SUVmax was observed in ovarian cancer, followed by small cell lung cancer, desmoplastic small round cell tumor, and adrenocortical carcinoma. When comparing radiotracer accumulation between primary tumors and metastases for the entire cohort, comparable SUVmax was recorded (P > 0.999), except for pulmonal findings (P = 0.013), indicative for uniform CXCR4 expression among TL. For higher IRS, a weak, but statistically significant correlation with increased SUVmax was observed (ρ = 0.328; P = 0.018). In 42/103 (40.8%) scans, more than five TL were recorded, with 12/42 (28.6%) exhibiting SUVmax above 10, suggesting eligibility for CXCR4-targeted treatment in this subcohort., Conclusions: In a whole-body tumor read-out, a substantial portion of prevalent solid tumors demonstrated increased and uniform [68 Ga]Ga-pentixafor uptake, along with high image contrast. We also observed a respective link between in- and ex-vivo CXCR4 expression, suggesting high specificity of the PET agent. Last, a fraction of patients with [68 Ga]Ga-pentixafor-positive tumor burden were rendered potentially suitable for CXCR4-directed therapy., (© 2023. The Author(s).)- Published
- 2024
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67. Prognostic Performance of RECIP 1.0 Based on [ 18 F]PSMA-1007 PET in Prostate Cancer Patients Treated with [ 177 Lu]Lu-PSMA I&T.
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Hartrampf PE, Hüttmann T, Seitz AK, Kübler H, Serfling SE, Higuchi T, Schlötelburg W, Michalski K, Gafita A, Rowe SP, Pomper MG, Buck AK, and Werner RA
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- Humans, Male, Dipeptides adverse effects, Heterocyclic Compounds, 1-Ring adverse effects, Lutetium, Positron Emission Tomography Computed Tomography methods, Prognosis, Retrospective Studies, Treatment Outcome, Niacinamide analogs & derivatives, Oligopeptides, Prostate-Specific Antigen, Prostatic Neoplasms, Castration-Resistant diagnostic imaging, Prostatic Neoplasms, Castration-Resistant radiotherapy, Urea analogs & derivatives
- Abstract
In metastatic castration-resistant prostate cancer (mCRPC) patients treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), the recently proposed criteria for evaluating response to PSMA PET (RECIP 1.0) based on
68 Ga- and18 F-labeled PET agents provided prognostic information in addition to changes in prostate-specific antigen (PSA) levels. Our aim was to evaluate the prognostic performance of this framework for overall survival (OS) in patients undergoing RLT and imaged with [18 F]PSMA-1007 PET/CT and compare the prognostic performance with the PSA-based response assessment. Methods: In total, 73 patients with mCRPC who were scanned with [18 F]PSMA-1007 PET/CT before and after 2 cycles of RLT were retrospectively analyzed. We calculated the changes in serum PSA levels (ΔPSA) and quantitative PET parameters for the whole-body tumor burden (SUVmean , SUVmax , PSMA tumor volume, and total lesion PSMA). Men were also classified following the Prostate Cancer Working Group 3 (PCWG3) criteria for ΔPSA and RECIP 1.0 for PET imaging response. We performed univariable Cox regression analysis, followed by multivariable and Kaplan-Meier analyses. Results: Median OS was 15 mo with a median follow-up time of 14 mo. Univariable Cox regression analysis provided significant associations with OS for ΔPSA (per percentage, hazard ratio [HR], 1.004; 95% CI, 1.002-1.007; P < 0.001) and PSMA tumor volume (per unit, HR, 1.003; 95% CI, 1.000-1.005; P = 0.03). Multivariable Cox regression analysis confirmed ΔPSA (per percentage, HR, 1.004; 95% CI, 1.001-1.006; P = 0.006) as an independent prognosticator for OS. Kaplan-Meier analyses provided significant segregation between individuals with versus those without any PSA response (19 mo vs. 14 mo; HR, 2.00; 95% CI, 0.95-4.18; P = 0.04). Differentiation between patients with or without progressive disease (PD) was also feasible when applying PSA-based PCWG3 (19 mo vs. 9 mo for non-PD and PD, respectively; HR, 2.29; 95% CI, 1.03-5.09; P = 0.01) but slightly failed when applying RECIP 1.0 ( P = 0.08). A combination of both response systems (PCWG3 and RECIP 1.0), however, yielded the best discrimination between individuals without versus those with PD (19 mo vs. 8 mo; HR, 2.78; 95% CI, 1.32-5.86; P = 0.002). Conclusion: In patients with mCRPC treated with RLT and imaged with [18 F]PSMA-1007, frameworks integrating both the biochemical (PCWG3) and PET-based response (RECIP 1.0) may best assist in identifying subjects prone to disease progression., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2024
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68. Evaluating the Patterns of FAPI Uptake in the Shoulder Joint: a Preliminary Study Comparing with FDG Uptake in Oncological Studies.
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Matsusaka Y, Werner RA, Serfling SE, Buck AK, Kosmala A, Sasaki T, Weich A, and Higuchi T
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- Female, Humans, Middle Aged, Aged, Fluorodeoxyglucose F18, Gallium Radioisotopes, Positron Emission Tomography Computed Tomography, Shoulder Joint, Quinolines
- Abstract
Background: Fibroblast activation protein inhibitor (FAPI) targeting PET has been introduced as a novel molecular imaging modality for visualizing cancer-associated fibroblasts. There have also been reports suggesting incidental findings of localized accumulation in the shoulder joints. However, further characterization in a larger patient cohort is still lacking., Methods: 77 consecutive patients (28 females; mean age, 63.1 ± 11.6) who underwent Ga-68 FAPI-04 PET/CT for diagnosis of solid tumors were included. The incidence and localization of tracer uptake in shoulder joints were investigated and compared with available F-18 FDG scans serving as reference., Results: Ga-68 FAPI-04 uptake was evaluated in 77 patients (154 shoulder joints), of whom 54 subjects (108 shoulder joints) also had available F-18 FDG scans for head-to-head comparison. On FAPI-targeted imaging, 67/154 shoulders (43.5%) demonstrated increased radiotracer accumulation in target lesions, which were distributed as follows: acromioclavicular (AC) joints in 25/67 (37.3%), followed by glenohumeral and subacromial (GH + SA) joints in 23/67 (34.3%), or both (AC and GH + SA joints) in the remaining 19/67 (28.4%). Ga-68 FAPI-04 correlated with quantified F-18 FDG uptake (r = 0.69, p < 0.0001). Relative to the latter radiotracer, however, in-vivo FAP expression in the shoulders was significantly increased (Ga-68 FAPI-04, 4.7 ± 3.2 vs F-18 FDG, 3.6 ± 1.3, p < 0.001)., Conclusion: Our study revealed focal accumulation of Ga-68 FAPI-04 in the shoulders, particularly in the AC joints, with higher uptake compared to the inflammatory-directed PET radiotracer F-18 FDG in oncological studies. As a result, further trials are warranted to investigate the potential of FAPI-directed molecular imaging in identifying chronic remodeling in shoulder joints. This could have implications for initiating anti-FAP targeted photodynamic therapy based on PET signal strength., (© 2024. The Author(s).)
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- 2024
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69. Exploring Theranostic Avenues in Adrenocortical Carcinoma Using Chemokine Receptor and Prostate-Specific Membrane Antigen-Directed PET/CT.
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Hahner S, Higuchi T, Serfling SE, Samnick S, Fuss CT, Heinze B, Buck AK, Schirbel A, Fassnacht M, and Werner RA
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- Male, Humans, Precision Medicine, Positron Emission Tomography Computed Tomography, Prostate, Adrenocortical Carcinoma, Adrenal Cortex Neoplasms
- Abstract
Abstract: We report on an adrenocortical carcinoma (ACC) patient, which has exhausted previous treatment options and was scheduled for prostate-specific membrane antigen (PSMA)- and C-X-C motif chemokine receptor 4 (CXCR4)-targeted PET/CT. We identified PSMA-avid pulmonary metastases exhibiting modest radiotracer accumulation, while chemokine receptor PET/CT provided intense uptake. This dual-tracer molecular imaging approach revealed that chemokine receptor PET appears to be more suitable in patients with advanced ACC, indicating that CXCR4-directed radioligand therapy may be considered in such patients suffering from end-stage disease. Given its dismal prognosis, chemokine receptor-directed theranostics may therefore extend the therapeutic armamentarium as last-line option in advanced ACC., Competing Interests: Conflicts of interest and sources of funding: This study was partially supported by the Okayama University “RECTOR” Program, KAKENHI grant (22H03027) from the Japan Society for the Promotion of Science (T.H.), and the German Research Foundation (453989101, R.A.W., T.H.; 507803309, R.A.W.). This work was supported by the Deutsche Forschungsgemeinschaft (DFG AL 203/1-1 and CRC/Transregio 205 “The Adrenal: Central Relay in Health and Disease”). R.A.W. and A.K.B. have received speaker honoraria from Novartis/AAA and PentixaPharm. R.A.W. reports advisory board work for Novartis/AAA and Bayer. A.K.B. is a member of the advisory board of PentixaPharm. All other authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
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70. Comparison of PET/CT-based eligibility according to VISION and TheraP trial criteria in end-stage prostate cancer patients undergoing radioligand therapy.
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Michalski K, Kosmala A, Werner RA, Serfling SE, Seitz AK, Lapa C, Buck AK, and Hartrampf PE
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- Male, Humans, Retrospective Studies, Treatment Outcome, Fluorodeoxyglucose F18, Prostate pathology, Prostate-Specific Antigen, Dipeptides therapeutic use, Heterocyclic Compounds, 1-Ring therapeutic use, Lutetium therapeutic use, Positron Emission Tomography Computed Tomography methods, Prostatic Neoplasms, Castration-Resistant diagnostic imaging, Prostatic Neoplasms, Castration-Resistant radiotherapy, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
Background: Two randomized clinical trials demonstrated the efficacy of prostate-specific membrane antigen (PSMA) radioligand therapy (PSMA RLT) in metastatic castration-resistant prostate cancer (mCRPC). While the VISION trial used criteria within PSMA PET/CT for inclusion, the TheraP trial used dual tracer imaging including FDG PET/CT. Therefore, we investigated whether the application of the VISION criteria leads to a benefit in overall survival (OS) or progression-free survival (PFS) for men with mCRPC after PSMA RLT., Methods: Thirty-five men with mCRPC who had received PSMA RLT as a last-line option and who had undergone pretherapeutic imaging with FDG and [
68 Ga]Ga-PSMA I&T or [18 F]PSMA-1007 were studied. Therapeutic eligibility was retrospectively evaluated using the VISION and TheraP study criteria., Results: 26 of 35 (74%) treated patients fulfilled the VISION criteria (= VISION+) and only 17 of 35 (49%) fulfilled the TheraP criteria (= TheraP+). Significantly reduced OS and PFS after PSMA RLT was observed in patients rated VISION- compared to VISION+ (OS: VISION-: 3 vs. VISION+: 12 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.0-9.1, p < 0.01; PFS: VISION-: 1 vs. VISION+: 5 months, HR 2.7, 95% CI 1.0-7.8, p < 0.01). For patients rated TheraP-, no significant difference in OS but in PFS was observed compared to TheraP+ patients (OS: TheraP-: 5.5 vs. TheraP+: 11 months, HR 1.6, 95% CI 0.8-3.3, p = 0.2; PFS: TheraP-: 1 vs. TheraP+: 6 months, HR 2.2, 95% CI 1.0-4.5, p < 0.01)., Conclusion: Retrospective application of the inclusion criteria of the VISION study leads to a benefit in OS and PFS after PSMA RL, whereas TheraP criteria appear to be too strict in patients with end-stage prostate cancer. Thus, performing PSMA PET/CT including a contrast-enhanced CT as proposed in the VISION trial might be sufficient for treatment eligibility of end-stage prostate cancer patients., (© 2023. The Author(s).)- Published
- 2024
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71. Chemokine receptor-targeted PET/CT provides superior diagnostic performance in newly diagnosed marginal zone lymphoma patients: a head-to-head comparison with [ 18 F]FDG.
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Kosmala A, Duell J, Schneid S, Serfling SE, Higuchi T, Weich A, Lapa C, Hartrampf PE, Raderer M, Einsele H, Buck AK, Topp MS, Schlötelburg W, and Werner RA
- Subjects
- Humans, Fluorodeoxyglucose F18, Gallium Radioisotopes, Peptides, Cyclic, Positron-Emission Tomography, Radionuclide Imaging, Coordination Complexes, Positron Emission Tomography Computed Tomography methods
- Abstract
Background: In patients with marginal zone lymphoma (MZL), [
18 F]FDG PET/CT provided inconsistent diagnostic accuracy. C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in MZL and thus, may emerge as novel theranostic target. We aimed to evaluate the diagnostic performance of CXCR4-targeting [68 Ga]Ga-PentixaFor when compared to [18 F]FDG PET/CT in MZL., Methods: Thirty-two untreated MZL patients (nodal, n = 17; extranodal, n = 13; splenic, n = 2) received [68 Ga]Ga-PentixaFor and [18 F]FDG PET/CT within median 2 days. We performed a visual and quantitative analysis of the total lymphoma volume by measuring maximum/peak standardized uptake values (SUVmax/peak ), and calculating target-to-background ratios (TBR, defined as lesion-based SUVpeak divided by SUVmean from blood pool). Visual comparisons for both radiotracers were carried out for all target lesions (TL), and quantitative analysis of concordant TL evident on both scans. Last, MZL subtype analyses were also conducted., Results: On a patient-based level, [68 Ga]Ga-PentixaFor identified MZL manifestations in 32 (100%) subjects (vs. [18 F]FDG, 25/32 [78.1%]). Of the 256 identified TL, 127/256 (49.6%) manifestations were evident only on CXCR4-directed imaging, while only 7/256 (2.7%) were identified on [18 F]FDG but missed by [68 Ga]Ga-PentixaFor. In the remaining 122/256 (47.7%) concordant TL, [68 Ga]Ga-PentixaFor consistently provided increased metrics when compared to [18 F]FDG: SUVmax , 10.3 (range, 2.53-37.2) vs. 5.72 (2.32-37.0); SUVpeak , 6.23 (1.58-25.7) vs. 3.87 (1.54-27.7); P < 0.01, respectively. Concordant TL TBR on [68 Ga]Ga-PentixaFor (median, 3.85; range, 1.05-16.0) was also approximately 1.8-fold higher relative to [18 F]FDG (median, 2.08; range, 0.81-28.8; P < 0.01). Those findings on image contrast, however, were driven by nodal MZL (P < 0.01), and just missed significance for extranodal MZL (P = 0.06)., Conclusions: In newly diagnosed MZL patients, [68 Ga]Ga-PentixaFor identified more sites of disease when compared to [18 F]FDG, irrespective of MZL subtype. Quantitative PET parameters including TBR were also higher on [68 Ga]Ga-PentixaFor PET/CT, suggesting improved diagnostic read-out using chemokine receptor-targeted imaging., (© 2023. The Author(s).)- Published
- 2024
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72. C-X-C Motif Chemokine Receptor 4-Targeted Radioligand Therapy in Hematological Malignancies-Myeloablative Effects, Antilymphoma Activity, and Safety Profile.
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Dreher N, Dörrler AL, Kraus S, Higuchi T, Serfling SE, Samnick S, Einsele H, Grigoleit GU, Buck AK, and Werner RA
- Subjects
- Humans, Positron Emission Tomography Computed Tomography, Receptors, Chemokine, Tumor Lysis Syndrome, Hematologic Neoplasms radiotherapy, Hematopoietic Stem Cell Transplantation
- Abstract
Background: After C-X-C motif chemokine receptor 4 (CXCR4)-directed radioligand therapy (RLT), lymphoma patients are scheduled for conditioning therapy (CON) followed by hematopoietic stem cell transplantation (HSCT). We aimed to determine whether CXCR4-RLT can achieve bone marrow ablation and direct antilymphoma activity independent from CON/HSCT and also evaluated the safety profile of this theranostic approach in an acute setting., Patients and Methods: After CXCR4-directed 68 Ga-pentixafor PET/CT, 21 heavily pretreated patients with hematological malignancies underwent CXCR4-directed RLT using 90 Y-pentixather. The extent of myeloablative efficacy was determined by investigating hematologic laboratory parameters before RLT (day -1), at the day of RLT (day 0), 2 days after RLT (day 2), and before CON (median day 10). Serving as surrogate marker of antilymphoma activity, lactate dehydrogenase (LDH) levels were also assessed until CON. We also screened for laboratory-defined tumor lysis syndrome after the Cairo-Bishop definition and recorded acute laboratory adverse events using the Common Terminology Criteria for Adverse Events version 5.0., Results: After RLT, we observed a significant decline of leukocyte levels by 79.4% ± 18.7% till CON (granulocytes, drop by 70.3% ± 21%; platelets, reduction by 43.1% ± 36%; P ≤ 0.0005 vs day 0, respectively). After RLT, LDH levels already reached a peak at day 2, which was followed by a rapid decline thereafter (peak vs day of CON, P = 0.0006), indicating that 90 Y-pentixather exhibits direct antilymphoma activity. At day of CON, LDH levels were also significantly lower when compared with day -1 ( P = 0.04), suggestive for durable response mediated by RLT. No patient fulfilled the criteria of tumor lysis syndrome, whereas 25 laboratory adverse events attributable to CXCR4-directed treatment were identified (≥grade 3 in 2/25 [8%]). During further treatment course, all patients (100%) received HSCT., Conclusions: CXCR4-directed RLT causes effective myeloablation, which allows for HSCT. In addition, it also exerts direct antilymphoma activity independent of subsequent therapeutic steps, whereas safety profile was acceptable., Competing Interests: Conflicts of interest and sources of funding: This project is partially supported by the German Research Foundation (453989101, R.A.W. and T.H.; 507803309, R.A.W.). This work was sponsored in part by Okayama University “RECTOR” Program, KAKENHI grant (22H03027) from the Japan Society for the Promotion of Science (T.H.). R.A.W. has received speaker honoraria from Novartis/AAA and PentixaPharm, reports advisory board work for Novartis/AAA and Bayer, and is involved in 68 Ga-pentixafor PET imaging in marginal zone lymphoma (LYMFOR). A.K.B. has received speaker’s honoraria from PentixaPharm and is a member of the advisory board of PentixaPharm. All authors declare that there is no conflict of interest as well as consent for scientific analysis and publication., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2024
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73. Long-Term Nephrotoxicity of 177 Lu-PSMA Radioligand Therapy.
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Steinhelfer L, Lunger L, Cala L, Pfob CH, Lapa C, Hartrampf PE, Buck AK, Schäfer H, Schmaderer C, Tauber R, Brosch-Lenz J, Haller B, Meissner VH, Knorr K, Weber WA, and Eiber M
- Subjects
- Male, Humans, Retrospective Studies, Treatment Outcome, Prostate-Specific Antigen, Dipeptides adverse effects, Lutetium adverse effects, Heterocyclic Compounds, 1-Ring adverse effects, Prostatic Neoplasms, Castration-Resistant radiotherapy, Prostatic Neoplasms, Castration-Resistant pathology
- Abstract
β-emitting
177 Lu targeting prostate-specific membrane antigen (PSMA) is an approved treatment option for metastatic castration-resistant prostate cancer. Data on its long-term nephrotoxicity are sparse. This study aimed to retrospectively evaluate post-177 Lu-PSMA estimated glomerular filtration rate (eGFR) dynamics for at least 12 mo in a cohort of metastatic castration-resistant prostate cancer patients. Methods: The institutional databases of 3 German tertiary referral centers identified 106 patients who underwent at least 4 cycles of177 Lu-PSMA and had at least 12 mo of eGFR follow-up data. eGFR (by the Chronic Kidney Disease Epidemiology Collaboration formula) at 3, 6, and 12 mo after177 Lu-PSMA radioligand therapy was estimated using monoexponentially fitted curves through available eGFR data. eGFR changes were grouped (≥15%-<30%, moderate; ≥30%-<40%, severe; and ≥40%, very severe). Associations between eGFR changes (%) and nephrotoxic risk factors, prior treatment lines, and number of177 Lu-PSMA cycles were analyzed using multivariable linear regression. Results: At least moderate eGFR decreases were present in 45% (48/106) of patients; of those, nearly half (23/48) had a severe or very severe eGFR decrease. A higher number of risk factors at baseline (-4.51, P = 0.03) was associated with a greater eGFR decrease. Limitations of the study were the retrospective design, lack of a control group, and limited number of patients with a follow-up longer than 1 y. Conclusion: A considerable proportion of patients may experience moderate or severe decreases in eGFR 1 y from initiation of177 Lu-PSMA. A higher number of risk factors at baseline seems to aggravate loss of renal function. Further prospective trials are warranted to estimate the nephrotoxic potential of177 Lu-PSMA., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2024
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74. PSMA PET/CT for Response Assessment of 177 Lu-PSMA Therapy.
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Hartrampf PE, Serfling SE, Michalski K, Buck AK, and Werner RA
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- Male, Humans, Prospective Studies, Magnetic Resonance Imaging, Positron Emission Tomography Computed Tomography methods, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms radiotherapy
- Abstract
Prostate-specific membrane antigen (PSMA) PET/CT has been widely integrated into the management of prostate cancer (PCa) patients with biochemical recurrence, is increasingly used for initial staging in high-risk patients prior to surgery or to identify candidates for PSMA-targeted radioligand therapy (RLT). To date, monitoring response in PCa patients in prospective studies remains the domain of conventional imaging, such as magnetic resonance/CT or bone scintigraphy. With the increasing use of PSMA-targeted PET/CT in PCa, however, varying criteria based on molecular imaging have been established to define progressive disease, including "PSMA PET Progression Criteria," "Response evaluation criteria in PSMA PET/CT (RECIP 1.0)" or consensus statements of respective societies. In the present review, we will discuss the current status of PSMA PET/CT for response monitoring, focusing on PSMA RLT with [
177 Lu]Lu-labeled PSMA ligands, along with a head-to-head comparison of recently published response criteria., Competing Interests: Declaration of Competing Interest RAW, AKB, and KM have received speaker honoraria from Novartis/AAA and PentixaPharm. RAW reports advisory board work for Novartis/AAA and Bayer. All other authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2024
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75. Gallium-68-Labeled KISS1-54 Peptide for Mapping KISS1 Receptor via PET: Initial Evaluation in Human Tumor Cell Lines and in Tumor-Bearing Mice.
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Israel I, Riehl G, Butt E, Buck AK, and Samnick S
- Abstract
Kisspeptins (KPs, KISS1) and their receptor (KISS1R) play a pivotal role as metastasis suppressor for many cancers. Low or lost KP expression is associated with higher tumor grade, increased metastatic potential, and poor prognosis. Therefore, KP expression has prognostic relevance and correlates with invasiveness in cancers. Furthermore, KISS1R represents a very promising target for molecular imaging and therapy for KISS1R-expressing tumors. The goal of this study was to evaluate the developed KISS1-54 derivative, [
68 Ga]KISS1-54, as a PET-imaging probe for KISS1R-expressing tumors. The NODAGA-KISS1-54 peptide was labeled by Gallium-68, and the stability of the resulting [68 Ga]KISS1-54 evaluated in injection solution and human serum, followed by an examination in different KISS1R-expressing tumor cell lines, including HepG2, HeLa, MDA-MB-231, MCF7, LNCap, SK-BR-3, and HCT116. Finally, [68 Ga]KISS1-54 was tested in LNCap- and MDA-MB-231-bearing mice, using µ-PET, assessing its potential as an imaging probe for PET. [68 Ga]KISS1-54 was obtained in a 77 ± 7% radiochemical yield and at a >99% purity. The [68 Ga]KISS1-54 cell uptake amounted to 0.6-4.4% per 100,000 cells. Moreover, the accumulation of [68 Ga]KISS1-54 was effectively inhibited by nonradioactive KISS1-54. In [68 Ga]KISS1-54-PET, KISS1R-positive LNCap-tumors were clearly visualized as compared to MDA-MB-231-tumor implant with predominantly intracellular KISS1R expression. Our first results suggest that [68 Ga]KISS1-54 is a promising candidate for a radiotracer for targeting KISS1R-expressing tumors via PET.- Published
- 2023
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76. Radiopharmaceuticals for Treatment of Adrenocortical Carcinoma.
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Michalski K, Schlötelburg W, Hartrampf PE, Kosmala A, Buck AK, Hahner S, and Schirbel A
- Abstract
Adrenocortical carcinoma (ACC) represents a rare tumor entity with limited treatment options and usually rapid tumor progression in case of metastatic disease. As further treatment options are needed and ACC metastases are sensitive to external beam radiation, novel theranostic approaches could complement established therapeutic concepts. Recent developments focus on targeting adrenal cortex-specific enzymes like the theranostic twin [
123/131 I]IMAZA that shows a good image quality and a promising therapeutic effect in selected patients. But other established molecular targets in nuclear medicine such as the C-X-C motif chemokine receptor 4 (CXCR4) could possibly enhance the therapeutic regimen as well in a subgroup of patients. The aims of this review are to give an overview of innovative radiopharmaceuticals for the treatment of ACC and to present the different molecular targets, as well as to show future perspectives for further developments since a radiopharmaceutical with a broad application range is still warranted.- Published
- 2023
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77. Chemokine Receptor PET/CT Provides Relevant Staging and Management Changes in Marginal Zone Lymphoma.
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Duell J, Buck AK, Hartrampf PE, Schlötelburg W, Schneid S, Weich A, Dreher N, Lapa C, Kircher M, Higuchi T, Samnick S, Serfling SE, Raderer M, Rasche L, Einsele H, Topp MS, Kosmala A, and Werner RA
- Subjects
- Humans, Retrospective Studies, Prognosis, Proportional Hazards Models, Fluorodeoxyglucose F18, Neoplasm Staging, Positron Emission Tomography Computed Tomography methods, Lymphoma, B-Cell, Marginal Zone pathology
- Abstract
Because of gastral and extranodal manifestations, guideline-compatible diagnostic work-up of marginal zone lymphoma is challenging. We aimed to determine the diagnostic performance of C-X-C motif chemokine receptor 4 (CXCR4)-directed PET/CT compared with routine diagnostics, along with PET/CT-based retrospective changes in therapeutic management. The predictive potential of the PET signal was also investigated, and the number of patients eligible for CXCR4-directed radioligand therapy in a theranostic setting was determined. Methods: For this study, 100 marginal zone lymphoma patients underwent CXCR4-directed PET/CT. We compared staging results and treatment decisions from molecular imaging with respective results from guideline-compatible work-up (CT, esophagogastroduodenoscopy, and bone marrow-derived biopsy). Prognostic performance of the in vivo CXCR4 PET signal for progression-free survival (PFS) was evaluated (using log-rank test and Kaplan-Meier curves). Results: Relative to CT, CXCR4-directed imaging led to Ann Arbor (AA) staging changes for 27 of 100 patients (27.0%). Among those, clinically relevant upstaging from AA I or AA II to AA III or AA IV was observed for 23 patients (85.2%), along with respective changes in therapeutic management (escalation, 6/23 [26.1%]; deescalation, 17/23 [73.9%]). CXCR4 PET/CT yielded diagnostic accuracy of 94.0% relative to esophagogastroduodenoscopy and 76.8% relative to bone marrow-derived biopsy. An increased CXCR4 PET signal was linked to shorter PFS (707 d vs. median PFS not reached; hazard ratio, 3.18; 95% CI, 1.37-7.35; P = 0.01). CXCR4-directed radioligand therapy would have been feasible for 18 of 100 patients (18.0%). Conclusion: Relative to CT, CXCR4-directed PET/CT led to AA changes for 27 of 100 patients. Chemokine receptor PET/CT may improve current diagnostic algorithms and influence management relative to CT alone, potentially obviating some biopsies., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)
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- 2023
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78. Role of Functional SPECT and PET in Renal Emergencies.
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Higuchi T, Hartrampf PE, Buck AK, Pomper MG, Rowe SP, Serfling SE, and Werner RA
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- Humans, Tomography, Emission-Computed, Single-Photon, Positron-Emission Tomography methods, Radionuclide Imaging, Emergencies, Kidney diagnostic imaging
- Abstract
Renal scintigraphy is a centerpiece of nuclear medicine and is also commonly applied for (peri-)acute care. In this regard, referrals by the treating physician include: I.) acute obstructions caused by gradual and infiltrative tumor growth or renal off-target effects under anti-tumor treatment, II.) functional issues in infants, for example, structural abnormalities such as duplex kidneys or uroliths in adults, which can also trigger III.) Infections of renal parenchyma. Renal radionuclide imaging is also requested due to IV.) acute trauma to the abdomen, for example, to assess renal scarring or upon further follow-up after reconstructive surgery. We will discuss clinical applications of (peri-)acute renal scintigraphy, along with future prospects on the use of more advanced nuclear imaging techniques such as renal positron emission tomography., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. RAW has received speaker honoraria from PentixaPharm and Novartis., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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79. Diagnostic efficacy of C-X-C motif chemokine receptor 4-directed PET/CT in newly diagnosed head and neck squamous cell carcinoma - a head-to-head comparison with [ 18 F]FDG.
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Zhi Y, Werner RA, Schirbel A, Higuchi T, Buck AK, Kosmala A, Bley TA, Hagen R, Hackenberg S, Rosenwald A, Scherzad A, Gerhard-Hartmann E, and Serfling SE
- Abstract
Background: The aim of this study was to determine the read-out capabilities of the novel C-X-C motif chemokine receptor 4 (CXCR4)-targeting radiotracer [
68 Ga]Ga-PentixaFor compared to the reference radiotracer [18 F]FDG in untreated individuals with head and neck squamous cell carcinoma (HNSCC)., Material and Methods: 12 patients with histologically confirmed HNSCC were scheduled for [18 F]FDG and [68 Ga]Ga-PentixaFor PET/CT. Maximum standardized uptake values (SUVmax ) and target-to-background ratios (TBR) were applied with vena cava superior serving as reference. In addition, we compared [68 Ga]Ga-PentixaFor-PET findings with immunohistochemical (IHC) results of CXCR4 expression., Results: On visual assessment, [18 F]FDG identified more sites of disease, with increased detection rates for both the primary tumor ([18 F]FDG, 12/12 [100%] vs. [68 Ga]Ga-PentixaFor, 10/12 [83%]) and LN metastases ([18 F]FDG, 9/12 [75%] vs. [68 Ga]Ga-PentixaFor, 8/12 [67%]). Indicative for improved image contrast using [18 F]FDG, quantification showed a higher TBR for the latter radiotracer, when compared to [68 Ga]Ga-PentixaFor for all lesions ([18 F]FDG, 11.7 ± 8.5 vs. [68 Ga]Ga-PentixaFor, 4.3 ± 1.3; P=0.03), primary tumors ([18 F]FDG, 13.6 ± 8.7 vs. [68 Ga]Ga-PentixaFor, 4.4 ± 1.4; P<0.01), and LN lesions ([18 F]FDG, 9.3 ± 10.6 vs. [68 Ga]Ga-PentixaFor, 4.7 ± 1.5; P=0.3). IHC showed variable CXCR4 expression in the primary and LN, along with no associations between ex-vivo CXCR4 upregulation and [68 Ga]Ga-PentixaFor-based TBR (R=0.33, P=0.39) or SUVmax (R=0.44, P=0.2). Of note, IHC also revealed heterogeneous expression of CXCR4 in immune cells in the tumor microenvironment and in germinal centers, indicative for inflammatory reactions., Conclusions: In HNSCC, [18 F]FDG demonstrated superior diagnostic performance relative to [68 Ga]Ga-PentixaFor, in particular for assessment of the primary. Based on the IHC analyses, these findings may be explained by CXCR4 upregulation not only by tumor but also by immune cells in the tumor microenvironment., Competing Interests: R.A.W. has received speaker honoraria from PentixaPharm and is involved in [68Ga]Ga-Pentixafor PET Imaging in PAN Cancer (FORPAN), sponsored and planned by PentixaPharm., (AJNMMI Copyright © 2023.)- Published
- 2023
80. Early biochemical and radiographic response after one cycle of [ 177 Lu]Lu-PSMA I&T radioligand therapy in metastatic castration-resistant prostate cancer patients.
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Cytawa W, Hendel R, Tomasik B, Weinzierl FX, Bley T, Jassem J, Schirbel A, Buck AK, Bundschuh RA, Hartrampf PE, Werner RA, and Lapa C
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- Male, Humans, Retrospective Studies, Treatment Outcome, Prostate-Specific Antigen, Dipeptides therapeutic use, Heterocyclic Compounds, 1-Ring therapeutic use, Lutetium therapeutic use, Prostatic Neoplasms, Castration-Resistant diagnostic imaging, Prostatic Neoplasms, Castration-Resistant radiotherapy, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
Purpose: The aim of this study was to investigate very early radiographic PSMA PET response after one cycle of [
177 Lu]Lu-PSMA I&T radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC) and to assess its role in predicting overall response and survival., Methods: This retrospective study enrolled 40 mCRPC patients who were treated with a median of 3 (2-9) [177 Lu]Lu-PSMA I&T RLT cycles. Biochemical response was based on the relative change of serum PSA according to PCWG3 criteria, while radiographic response referred to the relative change of PSMA-derived total viable tumor volumes expressed as total lesion PSMA (TLP)., Results: After one cycle of RLT, biochemical partial response (PR) was seen in 8/40 (20.0%), stable disease (SD) in 22/40 (55.0%), and progressive disease (PD) in 10/40 (25%) patients. In PSMA PET, very early molecular PR was observed in 12 (30.0%), SD in 19 (47.5%), and PD in 9 (22.5%) subjects. The PSA and TLP nadir were achieved after a median of 1 (1-5) and 2 (1-6) cycles, respectively. Nineteen (47.5%) patients showed overall biochemical PR, 11 (27.5%) had SD, and 10 (25%) experienced PD. In PSMA-directed PET, 4 patients experienced molecular complete response (CR), 24 (60.0%) had PR, 4 (10.0%) SD, and 8 (20.0%) PD. Early biochemical or radiographic response was not associated with longer overall survival (OS). Overall biochemical responders had a nearly significantly longer median OS (22.7 months) than non-responders (14.4 months, p = 0.08). Early PSA progression was associated with shorter OS (12.2 months), compared to biochemical SD/PR (18.7 months, p = 0.09)., Conclusion: In this retrospective cohort, there was no association between early PSMA PET radiographic response and overall survival; hence, treatment should not be prematurely discontinued. In contrast, early PSA progression after one cycle of [177 Lu]Lu-PSMA I&T RLT was an indicator of overall progression and poor clinical outcome., (© 2023. The Author(s).)- Published
- 2023
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81. Test-retest repeatability of organ uptake on PSMA-targeted 18 F-DCFPyL PET/CT in patients with prostate cancer.
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Werner RA, Lütje S, Habacha B, Bundschuh L, Higuchi T, Buck AK, Kosmala A, Lapa C, Essler M, Lodge MA, Pienta KJ, Eisenberger MA, Markowski MC, Gorin MA, Pomper MG, Rowe SP, and Bundschuh RA
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- Humans, Male, Lysine, Prospective Studies, Urea, Positron Emission Tomography Computed Tomography methods, Prostatic Neoplasms diagnostic imaging
- Abstract
Objectives: We evaluated
18 F-DCFPyL test-retest repeatability of uptake in normal organs., Methods: Twenty-two prostate cancer (PC) patients underwent two18 F-DCFPyL PET scans within 7 days within a prospective clinical trial (NCT03793543). In both PET scans, uptake in normal organs (kidneys, spleen, liver, and salivary and lacrimal glands) was quantified. Repeatability was determined by using within-subject coefficient of variation (wCOV), with lower values indicating improved repeatability., Results: For SUVmean , repeatability was high for kidneys, spleen, liver, and parotid glands (wCOV, range: 9.0%-14.3%) and lower for lacrimal (23.9%) and submandibular glands (12.4%). For SUVmax , however, the lacrimal (14.4%) and submandibular glands (6.9%) achieved higher repeatability, while for large organs (kidneys, liver, spleen, and parotid glands), repeatability was low (range: 14.1%-45.2%)., Conclusion: We found acceptable repeatability of uptake on18 F-DCFPyL PET for normal organs, in particular for SUVmean in the liver or parotid glands. This may have implications for both PSMA-targeted imaging and treatment, as patient selection for radioligand therapy and standardized frameworks for scan interpretation (PROMISE, E-PSMA) rely on uptake in those reference organs., (© 2023 The Authors. The Prostate published by Wiley Periodicals LLC.)- Published
- 2023
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82. Breast cancer survivorship experiences among Black women.
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Ko NY, Fikre TG, Buck AK, Restrepo E, and Warner ET
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- Humans, Female, Middle Aged, Survivorship, Quality of Life, Breast, Breast Neoplasms therapy, Cancer Survivors
- Abstract
Background: Black women experience significant disparities in breast cancer across the care continuum, including survivorship. Ensuring that Black women obtain high-quality follow-up care is critical but understudied. This study was aimed at understanding the experiences and needs of Black women during breast cancer survivorship., Methods: Black patients diagnosed with invasive breast cancer within the past 5 years were invited to participate in a focus group and complete a survey. Focus groups examined the following: (1) the transition from active treatment to survivorship; (2) interactions with health care providers; (3) survivorship experiences, information needs, and preferences; and (4) existing educational materials. Results were thematically coded and analyzed for main themes. Surveys collected information on sociodemographics, health care experiences, quality of life, lifestyle, and education needs., Results: The study enrolled 53 participants, 43 of whom completed a survey and participated in one of 11 focus groups. The median age was 54 years, 44% had private insurance, 81% were English speaking, and 86% had completed their treatment more than a year before. Participants identified the importance of relationships with health care providers, gaps in survivorship care, experiences with cancer-related symptoms, challenges with mental health, worry about recurrence, body image, cancer financial toxicity, and coping through religion and spirituality. Unmet needs were centered around preparation for long-term symptoms, diet and physical activity, emotional support, and more explanations of information resources. Participants reported preferences for educational videos, personal stories, and culturally relevant content., Conclusions: Some Black breast cancer survivors may have specific challenges and preferences. Supportive interventions that address these concerns can be responsive and help to ameliorate disparities., (© 2023 American Cancer Society.)
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- 2023
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83. SUV mean on baseline [ 18 F]PSMA-1007 PET and clinical parameters are associated with survival in prostate cancer patients scheduled for [ 177 Lu]Lu-PSMA I&T.
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Hartrampf PE, Hüttmann T, Seitz AK, Kübler H, Serfling SE, Schlötelburg W, Michalski K, Rowe SP, Pomper MG, Buck AK, Eberlein U, and Werner RA
- Subjects
- Male, Humans, Treatment Outcome, Retrospective Studies, Dipeptides therapeutic use, Positron-Emission Tomography, Heterocyclic Compounds, 1-Ring therapeutic use, Lutetium therapeutic use, Prostate-Specific Antigen therapeutic use, Prostatic Neoplasms, Castration-Resistant diagnostic imaging, Prostatic Neoplasms, Castration-Resistant radiotherapy, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
Background: Quantification of [
68 Ga]-labeled PSMA PET predicts response in patients with prostate cancer (PC) who undergo PSMA-targeted radioligand therapy (RLT). Given the increasing use [18 F]-labeled radiotracers, we aimed to determine whether the uptake derived from [18 F]PSMA-1007 PET can also identify responders and to assess its prognostic value relative to established clinical parameters., Methods: We retrospectively analyzed 103 patients with metastatic, castration-resistant PC who were treated with [177 Lu]Lu-PSMA I&T. We calculated SUVmean , SUVmax , PSMA-avid tumor volume (TV), and total lesion PSMA (defined as PSMA-TV*SUVmean ) on pre-therapeutic [18 F]PSMA-1007 PET. Laboratory values for hemoglobin, C-reactive protein (CRP), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alkaline phosphatase (AP) were also collected prior to RLT. We performed univariable Cox regression followed by multivariable and Kaplan-Meier analyses with overall survival (OS) serving as endpoint. Last, we also computed a risk factor (RF) model including all items reaching significance on multivariable analysis to determine whether an increasing number of RFs can improve risk stratification., Results: A total of 48 patients died and median OS was 16 months. On univariable Cox regression, SUVmean , CRP, LDH, hemoglobin, and the presence of liver metastases were significantly associated with OS. On multivariable Cox regression, the following significant prognostic factors for OS were identified: SUVmean (per unit, HR, 0.91; P = 0.04), the presence of liver metastases (HR, 2.37; P = 0.03), CRP (per mg/dl, HR, 1.13; P = 0.003), and hemoglobin (per g/dl, HR, 0.76; P < 0.01). Kaplan-Meier analysis showed significant separation between patients with a SUVmean below or above a median SUVmean of 9.4 (9 vs 19 months, HR 0.57; P = 0.03). Of note, patients with only one RF (median OS not reached) showed longest survival compared to patients with two (11 months; HR 2.43 95% CI 1.07-5.49, P = 0.02) or more than two RFs (7 months; HR 3.37 95% CI 1.62-7.03, P < 0.001)., Conclusion: A lower SUVmean derived from [18 F]PSMA-1007, higher CRP, lower hemoglobin, and the presence of liver metastases are associated with reduced OS in patients undergoing RLT. An early RF model also demonstrated that an increasing number of those factors is linked to worse outcome, thereby emphasizing the importance of clinical and imaging parameters for adequate risk stratification., (© 2023. The Author(s).)- Published
- 2023
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84. CXCR4-Directed Imaging and Endoradiotherapy in Desmoplastic Small Round Cell Tumors.
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Hartlapp I, Hartrampf PE, Serfling SE, Wild V, Weich A, Rasche L, Roth S, Rosenwald A, Mihatsch PW, Hendricks A, Wiegering A, Wiegering V, Hänscheid H, Schirbel A, Werner RA, Buck AK, Wester HJ, Einsele H, Kunzmann V, Lapa C, and Kortüm KM
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- Adolescent, Humans, Male, Female, Positron Emission Tomography Computed Tomography methods, Fluorodeoxyglucose F18, Gallium Radioisotopes, Transplantation, Autologous, Peptides, Cyclic, Receptors, CXCR4 metabolism, Hematopoietic Stem Cell Transplantation, Desmoplastic Small Round Cell Tumor diagnostic imaging, Desmoplastic Small Round Cell Tumor therapy, Coordination Complexes
- Abstract
Desmoplastic small round cell tumor (DSRCT) is a rare, radiosensitive, yet difficult-to-treat sarcoma subtype affecting predominantly male adolescents. Extensive intraperitoneal seeding is common and requires multimodal management. With no standard therapy established, the prognosis remains poor, and new treatment options are needed. We demonstrate the clinical potential of C-X-C motif chemokine receptor 4 (CXCR4)-directed imaging and endoradiotherapy in DSRCT. Methods: Eight male patients underwent dual-tracer imaging with [
18 F]FDG and CXCR4-directed [68 Ga]pentixafor PET/CT. A visual comparison of both tracers, along with uptake quantification in active DSRCT lesions, was performed. [68 Ga]pentixafor uptake was correlated with immunohistochemical CXCR4 expression on tumor cells. Four patients with end-stage progressive disease underwent CXCR4-based endoradiotherapy. We report the safety, response by RECIST 1.1, and survival after endoradiotherapy. Results: Uptake of [68 Ga]pentixafor in tumor lesions was demonstrated in all patients with DSRCT, providing diagnostic power comparable to [18 F]FDG PET. Corresponding CXCR4 expression was confirmed by immunohistochemistry in all DSRCT biopsies. Finally, 4 patients were treated with CXCR4-directed [90 Y]endoradiotherapy, 3 in a myeloablative dose range with subsequent autologous stem cell transplantation. All 3 required transfusions, and febrile neutropenia occurred in 2 patients (resulting in 1 death). Notably, severe nonhematologic adverse events were absent. We observed signs of response in all 3 patients, translating into disease stabilization in 2 patients for 143 and 176 d, respectively. In the third patient, postmortem autopsy confirmed a partial pathologic response. Conclusion: We validated CXCR4 as a diagnostic biomarker and a promising target for endoradiotherapy in DSRCT, demonstrated its feasibility, and provided the first evidence of its clinical efficacy., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2023
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85. Elevated Body Mass Index Is Associated with Improved Overall Survival in Castration-Resistant Prostate Cancer Patients Undergoing Prostate-Specific Membrane Antigen-Directed Radioligand Therapy.
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Hartrampf PE, Mihatsch PW, Seitz AK, Solnes LB, Rowe SP, Pomper MG, Kübler H, Bley TA, Buck AK, and Werner RA
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- Male, Humans, Body Mass Index, Prostate-Specific Antigen metabolism, Overweight chemically induced, Overweight complications, Overweight drug therapy, Prostate metabolism, Treatment Outcome, Lutetium therapeutic use, Retrospective Studies, Heterocyclic Compounds, 1-Ring therapeutic use, Dipeptides therapeutic use, Prostatic Neoplasms, Castration-Resistant radiotherapy, Prostatic Neoplasms, Castration-Resistant complications, Sarcopenia chemically induced, Sarcopenia complications, Sarcopenia drug therapy
- Abstract
In patients with prostate cancer scheduled for systemic treatment, being overweight is linked to prolonged overall survival (OS), whereas sarcopenia is associated with shorter OS. We investigated fat-related and body composition parameters in patients undergoing prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) to assess their predictive value for OS. Methods: Body mass index (BMI, in kg/m
2 ) and CT-derived body composition parameters (total, subcutaneous, visceral fat area, and psoas muscle area at the L3-L4 level) were determined for 171 patients scheduled for PSMA-directed RLT. After normalization for stature, the psoas muscle index was used to define sarcopenia. Outcome analysis was performed using Kaplan-Meier curves and Cox regression including fat-related and other clinical parameters (Gleason score, C-reactive protein [CRP], lactate dehydrogenase [LDH], hemoglobin, and prostate-specific antigen levels). The Harrell C-index was used for goodness-of-fit analysis. Results: Sixty-five patients (38%) had sarcopenia, and 98 patients (57.3%) had increased BMI. Relative to the 8-mo OS in normal-weight men (BMI < 25), overweight men (25 ≥ BMI > 30) and obese men (BMI ≥ 30) achieved a longer OS of 14 mo (hazard ratio [HR], 0.63; 95% CI, 0.40-0.99; P = 0.03) and 13 mo (HR, 0.47; 95% CI, 0.29-0.77; P = 0.004), respectively. Sarcopenia showed no impact on OS (11 vs. 12 mo; HR, 1.4; 95% CI, 0.91-2.1; P = 0.09). Most of the body composition parameters were tightly linked to OS on univariable analyses, with the highest C-index for BMI. In multivariable analysis, a higher BMI (HR, 0.91; 95% CI, 0.86-0.97; P = 0.006), lower CRP (HR, 1.09; 95% CI, 1.03-1.14; P < 0.001), lower LDH (HR, 1.08; 95% CI, 1.03-1.14; P < 0.001), and longer interval between initial diagnosis and RLT (HR, 0.95; 95% CI, 0.91-0.99; P = 0.02) were significant predictors of OS. Conclusion: Increased fat reserves assessed by BMI, CRP, LDH, and interval between initial diagnosis and RLT, but not CT-derived body composition parameters, were relevant predictors for OS. As BMI can be altered, future research should investigate whether a high-calorie diet before or during PSMA RLT may improve OS., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2023
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86. Lymphoma-Sink Effect in Marginal Zone Lymphoma Based on CXCR4-Targeted Molecular Imaging.
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Kosmala A, Seifert S, Schneid S, Dreher N, Higuchi T, Weich A, Serfling SE, Hartrampf PE, Einsele H, Buck AK, Topp MS, Duell J, and Werner RA
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- Humans, Positron Emission Tomography Computed Tomography methods, Retrospective Studies, Peptides, Cyclic, Molecular Imaging, Receptors, CXCR4, Coordination Complexes, Neoplasms, Lymphoma, B-Cell, Marginal Zone diagnostic imaging, Hematologic Neoplasms
- Abstract
Purpose: Recent studies investigating a tumor-sink effect in solid tumors reported on decreasing uptake in normal organs in patients with higher tumor burden. This phenomenon, however, has not been evaluated yet for theranostic radiotracers applied to hematological neoplasms. As such, we aimed to determine a potential "lymphoma-sink effect" in patients with marginal zone lymphoma (MZL) imaged with C-X-C motif chemokine receptor (CXCR) 4-directed PET/CTs., Procedures: We retrospectively analyzed 73 patients with MZL who underwent CXCR4-directed [
68 Ga]Ga-PentixaFor PET/CT. Normal unaffected organ uptake (heart, liver, spleen, bone marrow, kidneys) was quantified using volumes of interests (VOIs) and mean standardized uptake values (SUVmean ) were derived. MZL manifestations were also segmented to determine the maximum and peak standardized uptake values SUV (SUVmax/peak ) and volumetric parameters, including lymphoma volume (LV), and fractional lymphoma activity (FLA, defined as LV*SUVmean of lymphoma burden). This approach resulted in 666 VOIs to capture the entire MZL manifestation load. We used Spearman's rank correlations to determine associations between organ uptake and CXCR4-expressing lymphoma lesions., Results: We recorded the following median SUVmean in normal organs: heart, 1.82 (range, 0.78-4.11); liver, 1.35 (range, 0.72-2.99); bone marrow, 2.36 (range, 1.12-4.83); kidneys, 3.04 (range, 2.01-6.37); spleen, 5.79 (range, 2.07-10.5). No relevant associations between organ radiotracer uptake and MZL manifestation were observed, neither for SUVmax (ρ ≤ 0.21, P ≥ 0.07), SUVpeak (ρ ≤ 0.20, P ≥ 0.09), LV (ρ ≤ 0.13, P ≥ 0.27), nor FLA (ρ ≤ 0.15, P ≥ 0.33)., Conclusions: Investigating a lymphoma-sink effect in patients with hematological neoplasms, we observed no relevant associations between lymphoma burden and uptake in normal organs. Those observations may have therapeutic implications, e.g., for "cold" SDF1-pathway disrupting or "hot," CXCR4-directed radiolabeled drugs, as with higher lymphoma load, normal organ uptake seems to remain stable., (© 2023. The Author(s).)- Published
- 2023
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87. Molecular imaging of arterial fibroblast activation protein: association with calcified plaque burden and cardiovascular risk factors.
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Kosmala A, Serfling SE, Michalski K, Lindner T, Schirbel A, Higuchi T, Hartrampf PE, Derlin T, Buck AK, Weich A, and Werner RA
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- Humans, Positron Emission Tomography Computed Tomography, Risk Factors, Heart Disease Risk Factors, Molecular Imaging, Fibroblasts metabolism, Gallium Radioisotopes, Fluorodeoxyglucose F18, Cardiovascular Diseases diagnostic imaging, Plaque, Atherosclerotic diagnostic imaging, Plaque, Atherosclerotic metabolism, Vascular Calcification diagnostic imaging, Quinolines
- Abstract
Purpose: We aimed to assess prevalence, distribution, and intensity of in-vivo arterial wall fibroblast activation protein (FAP) uptake, and its association with calcified plaque burden, cardiovascular risk factors (CVRFs), and FAP-avid tumor burden., Methods: We analyzed 69 oncologic patients who underwent [
68 Ga]Ga-FAPI-04 PET/CT. Arterial wall FAP inhibitor (FAPI) uptake in major vessel segments was evaluated. We then investigated the associations of arterial wall uptake with calcified plaque burden (including number of plaques, plaque thickness, and calcification circumference), CVRFs, FAP-positive total tumor burden, and image noise (coefficient of variation, from normal liver parenchyma)., Results: High focal arterial FAPI uptake (FAPI +) was recorded in 64/69 (92.8%) scans in 800 sites, of which 377 (47.1%) exhibited concordant vessel wall calcification. The number of FAPI + sites per patient and (FAPI +)-derived target-to-background ratio (TBR) correlated significantly with the number of calcified plaques (FAPI + number: r = 0.45, P < 0.01; TBR: r = - 0.26, P = 0.04), calcified plaque thickness (FAPI + number: r = 0.33, P < 0.01; TBR: r = - 0.29, P = 0.02), and calcification circumference (FAPI + number: r = 0.34, P < 0.01; TBR: r = - 0.26, P = 0.04). In univariate analysis, only body mass index was significantly associated with the number of FAPI + sites (OR 1.06; 95% CI, 1.02 - 1.12, P < 0.01). The numbers of FAPI + sites and FAPI + TBR, however, were not associated with other investigated CVRFs in univariate and multivariate regression analyses. Image noise, however, showed significant correlations with FAPI + TBR (r = 0.30) and the number of FAPI + sites (r = 0.28; P = 0.02, respectively). In addition, there was no significant interaction between FAP-positive tumor burden and arterial wall FAPI uptake (P ≥ 0.13)., Conclusion: [68 Ga]Ga-FAPI-04 PET identifies arterial wall lesions and is linked to marked calcification and overall calcified plaque burden, but is not consistently associated with cardiovascular risk. Apparent wall uptake may be partially explained by image noise., (© 2023. The Author(s).)- Published
- 2023
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88. In-Vivo Somatostatin-Receptor Expression in Small Cell Lung Cancer as a Prognostic Image Biomarker and Therapeutic Target.
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Şen F, Sheikh GT, von Hinten J, Schindele A, Kircher M, Dierks A, Pfob CH, Serfling SE, Buck AK, Pelzer T, Higuchi T, Weich A, Bundschuh RA, Werner RA, and Lapa C
- Abstract
Background: Given the dismal prognosis of small cell lung cancer (SCLC), novel therapeutic targets are urgently needed. We aimed to evaluate whether SSTR expression, as assessed by positron emission tomography (PET), can be applied as a prognostic image biomarker and determined subjects eligible for peptide receptor radionuclide therapy (PRRT)., Methods: A total of 67 patients (26 females; age, 41-80 years) with advanced SCLC underwent SSTR-directed PET/computed tomography (somatostatin receptor imaging, SRI). SRI-avid tumor burden was quantified by maximum standardized uptake values (SUV
max ) and tumor-to-liver ratios (T/L) of the most intense SCLC lesion. Scan findings were correlated with progression-free (PFS) and overall survival (OS). In addition, subjects eligible for SSTR-directed radioligand therapy were identified, and treatment outcome and toxicity profile were recorded., Results: On a patient basis, 36/67 (53.7%) subjects presented with mainly SSTR-positive SCLC lesions (>50% lesions positive); in 10/67 patients (14.9%), all lesions were positive. The median SUVmax was found to be 8.5, while the median T/L was 1.12. SRI-uptake was not associated with PFS or OS, respectively (SUVmax vs. PFS, ρ = 0.13 with p = 0.30 and vs. OS, ρ = 0.00 with p = 0.97; T/L vs. PFS, ρ = 0.07 with p = 0.58 and vs. OS, ρ = -0.05 with p = 0.70). PRRT was performed in 14 patients. One patient succumbed to treatment-independent infectious complications immediately after PRRT. In the remaining 13 subjects, disease control was achieved in 5/13 (38.5%) with a single patient achieving a partial response (stable disease in the remainder). In the sub-group of responding patients, PFS and OS were 357 days and 480 days, respectively., Conclusions: SSTR expression as detected by SRI is not predictive of outcome in patients with advanced SCLC. However, it might serve as a therapeutic target in selected patients.- Published
- 2023
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89. Impact of CXCR4-Directed PET/CT on Staging and Proposed Oncologic Management in Patients With Digestive System Tumors.
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Weich A, Serfling SE, Schlötelburg W, Higuchi T, Hartrampf PE, Schirbel A, Heinrich M, Buck AK, Rowe SP, Kosmala A, and Werner RA
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- Humans, Positron Emission Tomography Computed Tomography methods, Retrospective Studies, Positron-Emission Tomography methods, Peptides, Cyclic, Receptors, CXCR4, Coordination Complexes, Digestive System Neoplasms
- Abstract
Purpose: To elucidate the influence of CXC motif chemokine receptor 4 (CXCR4)-directed imaging on staging and proposed oncologic management in patients with digestive system tumors compared with guideline-appropriate imaging (GAI)., Methods: From our PET/CT database, we retrospectively identified 37 patients with advanced digestive system tumors, which had been scheduled for CXCR4-targeted [ 68 Ga]Ga-pentixafor PET/CT for potential theranostic considerations. In all subjects, concurrent GAI was also available. Patients were afflicted with gastroenteropancreatic neuroendocrine neoplasms (21/37 [56.8%]), pancreatic duct adenocarcinoma (6/37 [16.2%]), cholangiocarcinoma (5/37 [13.5%]), hepatocellular carcinoma (4/37 [10.8%]), and colorectal carcinoma (1/37 [2.7%]). Staging results and impact on proposed oncologic management by a board-certified gastroenterologist were compared between GAI and [ 68 Ga]Ga-pentixafor PET/CT., Results: Relative to GAI, CXCR4-directed PET/CT resulted in staging changes in 14 of 37 patients (37.8%). Upstaging was seen in 1 of 14 patients (7.1%), whereas downstaging was recorded in the remaining 13 of 14 patients (92.9%). Among those, staging changes would not have triggered any changes in oncological management in 4 of 14 (28.6%). For the remaining 10 of 14 patients (71.4%), however, findings on [ 68 Ga]Ga-pentixafor PET/CT would have impacted subsequent clinical algorithm, including the necessity for further diagnostic steps or failure to initiate antitumor therapy., Conclusion: [ 68 Ga]Ga-pentixafor PET/CT missed tumor lesions in 13 patients with digestive system tumors, which would have led to inappropriate downstaging and clinical treatment of 10 patients. As such, our results do not support a more widespread use of [ 68 Ga]Ga-pentixafor PET/CT for clinical staging in those tumor entities., Competing Interests: Conflicts of interest and sources of funding: This project was partially supported by the Okayama University “RECTOR” Program, KAKENHI grant (21K19450) from the Japan Society for the Promotion of Science (to T.H.) and the German Research Foundation (507803309, to R.A.W.; 453989101, to R.A.W., T.H.). R.A.W. and A.K.B. have received speaker's honoraria from PentixaPharm. A.K.B. is a member of the advisory board of PentixaPharm. All other authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2023
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90. Theranostics in Hematooncology.
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Buck AK, Serfling SE, Kraus S, Samnick S, Dreher N, Higuchi T, Rasche L, Einsele H, and Werner RA
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- Humans, Precision Medicine, Positron Emission Tomography Computed Tomography, Radioimmunotherapy methods, Yttrium Radioisotopes therapeutic use, Lymphoma, Follicular drug therapy, Lymphoma, Follicular pathology, Lymphoma, Non-Hodgkin diagnostic imaging, Lymphoma, Non-Hodgkin radiotherapy, Lymphoma, B-Cell diagnostic imaging, Lymphoma, B-Cell radiotherapy
- Abstract
In the early 2000s, major clinical trials provided evidence of a favorable outcome from antibody-mediated radioimmunotherapy for hematologic neoplasms, which then led to Food and Drug Administration approval. For instance, the theranostic armamentarium for the referring hematooncologist now includes
90 Y-ibritumomab tiuxetan for refractory low-grade follicular lymphoma or transformed B-cell non-Hodgkin lymphoma, as well as131 I-tositumomab for rituximab-refractory follicular lymphoma. Moreover, the first interim results of the SIERRA phase III trial reported beneficial effects from the use of131 I-anti-CD45 antibodies (Iomab-B) in refractory or relapsed acute myeloid leukemia. During the last decade, the concept of theranostics in hematooncology has been further expanded by C-X-C motif chemokine receptor 4-directed molecular imaging. Beyond improved detection rates of putative sites of disease, C-X-C motif chemokine receptor 4-directed PET/CT also selects candidates for radioligand therapy using β-emitting radioisotopes targeting the identical chemokine receptor on the lymphoma cell surface. Such image-piloted therapeutic strategies provided robust antilymphoma efficacy, along with desired eradication of the bone marrow niche, such as in patients with T- or B-cell lymphoma. As an integral part of the treatment plan, such radioligand therapy-mediated myeloablation also allows one to line up patients for stem cell transplantation, which leads to successful engraftment during the further treatment course. In this continuing education article, we provide an overview of the current advent of theranostics in hematooncology and highlight emerging clinical applications., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2023
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91. Partial Response Upon Peptide Receptor Radionuclide Therapy in a Highly Proliferative Pancreatic Neuroendocrine Tumor.
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Weich A, Serfling SE, Rowe SP, Solnes LB, Buck AK, Higuchi T, and Werner RA
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- Humans, Radioactive Tracers, Positron Emission Tomography Computed Tomography, Pancreatic Neoplasms diagnostic imaging, Pancreatic Neoplasms therapy, Neuroendocrine Tumors diagnostic imaging, Neuroendocrine Tumors therapy, Receptors, Peptide metabolism, Receptors, Peptide therapeutic use, Receptors, Somatostatin metabolism, Receptors, Somatostatin therapeutic use
- Abstract
Abstract: We report on a patient diagnosed with an aggressive pancreatic neuroendocrine tumor (NET G3; Ki67 = 60%), who underwent pancreatic resection with partial removal of liver lesions. The patient refused chemotherapy. Dual-tracer imaging with 18 F-FDG and somatostatin receptor (SSTR)-targeted PET/CT was conducted. Radiotracer accumulation on both imaging modalities in bilobar hepatic lesions was observed. "Cold" somatostatin analogues with four cycles of peptide receptor radionuclide therapy (PRRT) were initiated, leading to partial response. Even in highly proliferative but differentiated G3 NET (Ki67>55%), SSTR expression in sites of disease should be evaluated, which may then allow PRRT, even as first-line systemic treatment., Competing Interests: Conflicts of interest and sources of funding: This project is partially supported by the Okayama University “RECTOR” Program (T.H.) and the German Research Foundation (507803309, R.A.W.; 453989101, R.A.W., T.H.). T.H. received a KAKENHI grant (22H03027) from the Japan Society for the Promotion of Science. R.A.W. has received speaker’s honoraria from Novartis and Triple A. The other authors have no conflicts to report., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2023
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92. Interobserver Agreement Rates on C-X-C Motif Chemokine Receptor 4-Directed Molecular Imaging and Therapy.
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Hartrampf PE, Kosmala A, Serfling SE, Bundschuh L, Higuchi T, Lapa C, Rowe SP, Matsusaka Y, Weich A, Buck AK, Bundschuh RA, and Werner RA
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- Humans, Observer Variation, Peptides, Cyclic, Gallium Radioisotopes, Receptors, Chemokine, Receptors, CXCR4, Positron Emission Tomography Computed Tomography methods, Coordination Complexes
- Abstract
Background: We aimed to evaluate the interobserver agreement rates in patients scanned with C-X-C motif chemokine receptor 4 (CXCR4)-directed PET/CT, including the rate of patients eligible for CXCR4-targeted radioligand therapy (RLT) based on scan results., Methods: Four independent observers reviewed 50 CXCR4-targeted [ 68 Ga]pentixafor PET/CT of patients with various solid cancers. On a visual level, the following items were assessed by each reader: overall scan impression, number of organ and lymph node (LN) metastases and number of affected organs and LN regions. For a quantitative investigation, readers had to choose a maximum of 3 target lesions, defined as largest in size and/or most intense uptake per organ compartment. Reference tissues were also quantified, including unaffected hepatic parenchyma and blood pool. Last, all observers had to decide whether patients were eligible for CXCR4-targeted RLT. Concordance rates were tested using intraclass correlation coefficients (ICCs). For interpretation, we applied the definition of Cicchetti (with 0.4-0.59 indicating fair; 0.6-0.74, good; 0.75-1, excellent agreement)., Results: On a visual level, fair agreement was achieved for an overall scan impression (ICC, 0.58; 95% confidence interval, 0.45-0.71). Organ and LN involvement (ICC, ≥0.4) demonstrated fair, whereas CXCR4 density and number of LN and organ metastases showed good agreement rates (ICC, ≥0.65). Number of affected organs and affected LN areas, however, showed excellent concordance (ICC, ≥0.76). Quantification in LN and organ lesions also provided excellent agreement rates (ICC, ≥0.92), whereas quantified uptake in reference organs provided fair concordance (ICC, ≥0.54). Again, excellent agreement rates were observed when deciding on patients eligible for CXCR4-RLT (ICC, 0.91; 95% confidence interval, 0.85-0.95)., Conclusions: In patients scanned with CXCR4-targeted PET/CT, we observed fair to excellent agreement rates for both molecular imaging and therapy parameters, thereby favoring a more widespread adoption of [ 68 Ga]pentixafor in the clinic., Competing Interests: Conflicts of interest and sources of funding: This project was partially supported by the Okayama University “RECTOR” Program, KAKENHI grant (21K19450) from the Japan Society for the Promotion of Science (T.H.) and the German Research Foundation (507803309, R.A.W.; 453989101, R.A.W., T.H.). R.A.W. and A.K.B. have received speaker's honoraria from PentixaPharm. A.K.B. is a member of the advisory board of PentixaPharm. R.A.B. is consultant to and has received speaker's honoraria from Bayer Healthcare (Leverkusen, Germany) and Eisai GmbH (Frankfurt, Germany). The other authors have no conflicts to report., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2023
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93. [ 18 F]FET-PET in children and adolescents with central nervous system tumors: does it support difficult clinical decision-making?
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Kertels O, Krauß J, Monoranu CM, Samnick S, Dierks A, Kircher M, Mihovilovic MI, Pham M, Buck AK, Eyrich M, Schlegel PG, Frühwald MC, Bison B, and Lapa C
- Subjects
- Male, Young Adult, Humans, Child, Adolescent, Child, Preschool, Retrospective Studies, Positron-Emission Tomography methods, Magnetic Resonance Imaging methods, Tyrosine, Clinical Decision-Making, Brain Neoplasms pathology, Glioma pathology, Central Nervous System Neoplasms diagnostic imaging
- Abstract
Purpose: Positron emission tomography (PET) with O-(2-[
18 F]fluoroethyl)-L-tyrosine ([18 F]FET) is a well-established tool for non-invasive assessment of adult central nervous system (CNS) tumors. However, data on its diagnostic utility and impact on clinical management in children and adolescents are limited., Methods: Twenty-one children and young adults (13 males; mean age, 8.6 ± 5.2 years; range, 1-19 at initial diagnosis) with either newly diagnosed (n = 5) or pretreated (n = 16) CNS tumors were retrospectively analyzed. All patients had previously undergone neuro-oncological work-up including cranial magnetic resonance imaging. In all cases, [18 F]FET-PET was indicated in a multidisciplinary team conference. The impact of PET imaging on clinical decision-making was assessed. Histopathology (n = 12) and/or clinical and imaging follow-up (n = 9) served as the standard of reference., Results: The addition of [18 F]FET-PET to the available information had an impact on further patient management in 14 out of 21 subjects, with avoidance of invasive surgery or biopsy in four patients, biopsy guidance in four patients, change of further treatment in another five patients, and confirmation of diagnosis in one patient., Conclusion: [18 F]FET-PET may provide important additional information for treatment guidance in pediatric and adolescent patients with CNS tumors., (© 2023. The Author(s).)- Published
- 2023
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94. Successful combination of selpercatinib and radioiodine after pretherapeutic dose estimation in RET-altered thyroid carcinoma.
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Werner RA, Sayehli C, Hänscheid H, Higuchi T, Serfling SE, Fassnacht M, Goebeler ME, Buck AK, and Kroiss M
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- Humans, Protein Kinase Inhibitors therapeutic use, Iodine Radioisotopes therapeutic use, Proto-Oncogene Proteins c-ret antagonists & inhibitors, Proto-Oncogene Proteins c-ret genetics, Pyrazoles therapeutic use, Pyridines therapeutic use, Thyroid Neoplasms drug therapy, Thyroid Neoplasms genetics, Thyroid Neoplasms pathology, Thyroid Neoplasms radiotherapy
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- 2023
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95. Lack of repeatability of radiomic features derived from PET scans: Results from a 18 F-DCFPyL test-retest cohort.
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Werner RA, Habacha B, Lütje S, Bundschuh L, Kosmala A, Essler M, Derlin T, Higuchi T, Lapa C, Buck AK, Pienta KJ, Lodge MA, Eisenberger MA, Markowski MC, Pomper MG, Gorin MA, Frey EC, Rowe SP, and Bundschuh RA
- Subjects
- Male, Humans, Prospective Studies, Reproducibility of Results, Positron-Emission Tomography, Contrast Media, Positron Emission Tomography Computed Tomography methods, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms pathology
- Abstract
Objectives: PET-based radiomic metrics are increasingly utilized as predictive image biomarkers. However, the repeatability of radiomic features on PET has not been assessed in a test-retest setting. The prostate-specific membrane antigen-targeted compound
18 F-DCFPyL is a high-affinity, high-contrast PET agent that we utilized in a test-retest cohort of men with metastatic prostate cancer (PC)., Methods: Data of 21 patients enrolled in a prospective clinical trial with histologically proven PC underwent two18 F-DCFPyL PET scans within 7 days, using identical acquisition and reconstruction parameters. Sites of disease were segmented and a set of 29 different radiomic parameters were assessed on both scans. We determined repeatability of quantification by using Pearson's correlations, within-subject coefficient of variation (wCOV), and Bland-Altman analysis., Results: In total, 230 lesions (177 bone, 38 lymph nodes, 15 others) were assessed on both scans. For all investigated radiomic features, a broad range of inter-scan correlation was found (r, 0.07-0.95), with acceptable reproducibility for entropy and homogeneity (wCOV, 16.0% and 12.7%, respectively). On Bland-Altman analysis, no systematic increase or decrease between the scans was observed for either parameter (±1.96 SD: 1.07/-1.30, 0.23/-0.18, respectively). The remaining 27 tested radiomic metrics, however, achieved unacceptable high wCOV (≥21.7%)., Conclusion: Many common radiomic features derived from a test-retest PET study had poor repeatability. Only Entropy and homogeneity achieved good repeatability, supporting the notion that those image biomarkers may be incorporated in future clinical trials. Those radiomic features based on high frequency aspects of images appear to lack the repeatability on PET to justify further study., (© 2023 The Authors. The Prostate published by Wiley Periodicals LLC.)- Published
- 2023
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96. Somatostatin Receptor-Directed PET/CT for Therapeutic Decision-Making and Disease Control in Patients Affected With Small Cell Lung Cancer.
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Serfling SE, Hartrampf PE, Zhi Y, Higuchi T, Kosmala A, Serfling J, Schirbel A, Hörning A, Buck AK, Weich A, and Werner RA
- Subjects
- Humans, Positron Emission Tomography Computed Tomography, Receptors, Somatostatin, Retrospective Studies, Small Cell Lung Carcinoma, Lung Neoplasms pathology, Neuroendocrine Tumors pathology
- Abstract
Background: Somatostatin receptor (SSTR)-targeted PET/CT is used for patients affected with small cell lung cancer (SCLC), but the clinical impact has not been elucidated yet. We aimed to determine whether SSTR PET/CT can trigger relevant therapeutic management changes in patients with SCLC and whether those modifications achieve disease control and are associated with prolonged survival., Methods: One hundred patients with SCLC received SSTR PET/CT. In a retrospective setting, we evaluated the diagnostic performance of PET versus CT and compared therapies before and after PET/CT to determine the impact of molecular imaging on treatment decision. We also determined the rate of disease control after therapeutic modifications and assessed survival in patients with and without changes in the therapeutic regimen., Results: Relative to CT, SSTR PET alone was superior for assessing bone lesions in 19 of 39 instances (49%). Treatment was modified in 59 of 100 (59%) after SSTR PET/CT. Forty of 59 (74.6%) received systemic treatment after hybrid imaging, with the remaining 15 of 59 (25.4%) scheduled for nonsystemic therapy. In the latter group, 13 of 15 (86.7%) received local radiation therapy or active surveillance (2/15 [13.3%]). Individuals scheduled for systemic treatment after imaging received peptide receptor radionuclide therapy (PRRT) in 28 of 44 (63.6%), followed by chemotherapy in 10 of 44 (22.7%), change in chemotherapy regimen in 3 of 44 (6.8%), and initiation of tyrosine kinase inhibitor in the remaining 3 of 44 (6.8%). Among patients with modified treatment, follow-up was available in 53 subjects, and disease control was achieved in 14 of 53 (26.4%). However, neither change to systemic treatment (155 days; hazard ratio, 0.94; 95% confidence interval, 0.53-1.67) nor change to nonsystemic treatment (210 days; hazard ratio, 0.67; 95% confidence interval, 0.34-1.34) led to a prolonged survival when compared with subjects with no change (171 days, P ≥ 0.22, respectively)., Conclusions: In patients with SCLC, SSTR-targeted hybrid imaging provides complementary information on the disease status. PET/CT led to management changes in 59% (mainly PRRT), achieving disease control in >26%. The high fraction of patients scheduled for PRRT may lay the foundation for combination strategies to achieve synergistic antitumor effects, for example, by combining PRRT plus recently introduced RNA polymerase II inhibitors., Competing Interests: Conflicts of interest and sources of funding: This study was partially funded by the German Research Foundation (453989101, T.H., R.A.W.; 507803309, R.A.W.); Okayama University (RECTOR Program, T.H.); and Japan Society for the Promotion of Science (22H03027, T.H.). R.A.W. has received speaker's honoraria from Triple A/Novartis. The other authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2023
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97. Complete Remission Upon Peptide Receptor Radionuclide Therapy in a G2 Pancreatic Neuroendocrine Tumor.
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Weich A, Serfling SE, Yi H, Buck AK, Higuchi T, and Werner RA
- Subjects
- Male, Humans, Middle Aged, Octreotide, Receptors, Somatostatin, Somatostatin, Radioisotopes, Neuroendocrine Tumors pathology, Pancreatic Neoplasms
- Abstract
Abstract: We report the case of a 52-year-old man affected with a metastasized neuroendocrine tumor (G2) of the pancreas. After surgical removal, follow-up imaging 36 months later revealed somatostatin receptor-positive liver lesions. Because of disease progression under cold somatostatin analogs 6 months later, peptide receptor radionuclide therapy was performed, that induced complete remission (CR), supporting the notion that "hot" somatostatin analogs can achieve CR even in patients affected with pancreatic G2 neuroendocrine tumor. Of note, such cases exhibiting CR upon peptide receptor radionuclide therapy are extremely rare and further investigations may pool those exceptional treatment responders., Competing Interests: Conflicts of interest and sources of funding: R.A.W. has received speaker's honoraria from Advanced Accelerator Applications. This project was partially supported by the Okayama University “RECTOR” Program (T.H.) and the German Research Foundation (507803309, R.A.W.; 453989101, R.A.W., T.H.). T.H. received a KAKENHI grant (21K19450) from the Japan Society for the Promotion of Science. The other authors have none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2023
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98. High Interobserver Agreement on PSMA PET/CT Even in the Absence of Clinical Data.
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Bundschuh RA, Lütje S, Bundschuh L, Lapa C, Higuchi T, Hartrampf PE, Gorin MA, Kosmala A, Buck AK, Pomper MG, Rowe SP, Essler M, Sheikh GT, and Werner RA
- Subjects
- Male, Humans, Observer Variation, Gallium Radioisotopes, Positron Emission Tomography Computed Tomography, Prostatic Neoplasms pathology
- Abstract
Background: Recommended by current guidelines, prostate-specific membrane antigen (PSMA)-directed PET/CT is increasingly used in men with prostate cancer (PC). We aimed to provide concordance rates using the PSMA reporting and data system (RADS) for scan interpretation and also determine whether such agreement rates are affected by available patient characteristics at time of scan., Patients and Methods: Sixty men with PC, who all underwent 68Ga-PSMA-11 PET/CT, were included. Three independent, experienced readers indicated general scan parameters (including overall scan result, organ or lymph node [LN] involvement, and appropriateness of radioligand therapy). Applying PSMA-RADS 1.0, observers also had to conduct RADS scoring on a target lesion (TL) and overall scan level. During the first read, observers were masked to all relevant clinical information, whereas on a second read, relevant patient characteristics were displayed, thereby allowing for determination of impact of available clinical information for scan interpretation. We used intraclass correlation coefficients (ICCs; with 95% confidence intervals [CIs]), which were then rated according to Cicchetti (0.4-0.59 fair, 0.6-0.74 good, and 0.75-1 excellent agreement)., Results: For general parameters, agreement rates were excellent, including an overall scan result (ICC, 0.85; 95% CI, 0.76-0.90), LN metastases (ICC, 0.89; 95% CI, 0.83-0.93), organ involvement (ICC, 0.82; 95% CI, 0.72-0.89), and indication for radioligand therapy (ICC, 0.94; 95% CI, 0.90-0.96). Overall RADS scoring was also excellent with an ICC of 0.91 (95% CI, 0.96-09.4). On a TL-based level, 251 different lesions were selected by the 3 observers (with 73 chosen by all 3 readers). RADS-based concordance rates were fair to excellent: all lesions, ICC of 0.78 (95% CI, 0.67-0.85); LN, ICC of 0.81 (95% CI, 0.63-0.92); skeleton, ICC of 0.55 (95% CI, 0-0.84); and prostate, ICC of 0.48 (95% CI, 0.17-0.78). When performing a second read displaying patient's characteristics, there were only minor modifications to the previously applied RADS scoring on a TL-based level (overall, n = 8): each reader 1 and 2 in 3/60 (5%) instances, and reader 3 in 2/60 (3.3%) instances. The main reason for recategorization (mainly upstaging) was provided information on PSA levels (4/8, 50%)., Conclusions: Applying PSMA-RADS, concordance rates were fair to excellent, whereas relevant modifications were rarely observed after providing clinical data. As such, even in the absence of patient information, standardized frameworks still provide guidance for reading PSMA PETs. Those findings may have implications for a high throughput in a busy PET practice, where patient details cannot always be retrieved at time of scan interpretation or in the context of clinical trials or central reviews in which readers may be blinded to clinical data., Competing Interests: Conflicts of interest and sources of funding: This work has been supported by the German Research Foundation (453989101, T.H., R.A.W.; 507803309, R.A.W.), the Okayama University (RECTOR Program, T.H.), and the Japan Society for the Promotion of Science (21K19450, T.H.). All other authors report no relationships that could be construed as a conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2023
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99. Allogeneic Hematopoietic Cell Transplantation Induces Vessel Wall Inflammation in Large Arteries.
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Serfling SE, Thaiss W, Wasserloos A, Rasche L, Kortüm KM, Kraus S, Higuchi T, Rowe SP, Kircher M, Buck AK, Einsele H, Beer AJ, Lapa C, and Werner RA
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- 2023
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100. C-X-C Motif Chemokine Receptor 4-Targeted Radioligand Therapy in Patients with Advanced T-Cell Lymphoma.
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Buck AK, Grigoleit GU, Kraus S, Schirbel A, Heinsch M, Dreher N, Higuchi T, Lapa C, Hänscheid H, Samnick S, Einsele H, Serfling SE, and Werner RA
- Subjects
- Female, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Receptors, Chemokine, Treatment Outcome, Hematopoietic Stem Cell Transplantation, Lymphoma, T-Cell, Lymphoma, T-Cell, Peripheral
- Abstract
C-X-C motif chemokine receptor 4 (CXCR4)-targeted radioligand therapy (RLT) has already been applied to advanced blood cancers, such as multiple myeloma or diffuse large B-cell lymphoma. We present a series of patients with advanced T-cell lymphoma (TCL) who were scheduled for CXCR4-directed therapy as a conditioning regimen, followed by hematopoietic stem cell transplantation (HSCT). Methods: Four patients with advanced, heavily pretreated, and relapsed TCL (2 men, 2 women; median age, 50 y) without suitable alternative therapeutic options underwent CXCR4-directed PET and pretherapeutic dosimetry. We then conducted CXCR4-targeted RLT in combination with allogeneic (3/4, 75%) or autologous (1/4, 25%) HSCT. One patient also underwent radioimmunotherapy targeting CD66 to enhance therapeutic efficacy. We investigated safety, best response, progression-free survival, and overall survival. Results: Pretherapeutic dosimetry indicated lymphoma-absorbed doses of up to 33.2 Gy from CXCR4-targeted RLT. Except for 1 patient who developed tumor lysis syndrome along with transient grade 3 kidney failure, no acute toxicity, allergic reactions, or other adverse events were recorded during therapy. One patient developed septicemia and subsequently died 16 d after RLT, whereas engraftment was achieved in the remaining 3 patients (75%). During follow-up, a partial response was recorded in 1 of 3 patients (33.3%) and a complete metabolic response in the other two (66.7%, with 1 patient also receiving additional radioimmunotherapy). Median progression-free survival was 7 mo (range, 4-25 mo). After a median follow-up of 54 mo (range, 4-56 mo), 3 patients were still alive at the date of censoring. Conclusion: For advanced, heavily pretreated TCL, CXCR4-directed RLT may serve as an effective conditioning therapy before HSCT and can cause substantial antilymphoma activity, leading to a remarkable response in selected cases., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)
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- 2023
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