Publications by authors named "Uwe Haberkorn"

380 Publications

FAPI-74 PET/CT Using Either F-AlF or Cold-Kit Ga Labeling: Biodistribution, Radiation Dosimetry, and Tumor Delineation in Lung Cancer Patients.

J Nucl Med 2021 02 26;62(2):201-207. Epub 2020 Jun 26.

Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Ga-fibroblast activation protein inhibitors (FAPIs) 2, 4, and 46 have already been proposed as promising PET tracers. However, the short half-life of Ga (68 min) creates problems with manufacture and delivery. F (half-life, 110 min) labeling would result in a more practical large-scale production, and a cold-kit formulation would improve the spontaneous availability. The NOTA chelator ligand FAPI-74 can be labeled with both F-AlF and Ga. Here, we describe the in vivo evaluation of F-FAPI-74 and a proof of mechanism for Ga-FAPI-74 labeled at ambient temperature. In 10 patients with lung cancer, PET scans were acquired at 10 min, 1 h, and 3 h after administration of 259 ± 26 MBq of F-FAPI-74. Physiologic biodistribution and tumor uptake were semiquantitatively evaluated on the basis of SUV at each time point. Absorbed doses were evaluated using OLINDA/EXM, version 1.1, and QDOSE dosimetry software with the dose calculator IDAC-Dose, version 2.1. Identical methods were used to evaluate one examination after injection of 263 MBq of Ga-FAPI-74. The highest contrast was achieved in primary tumors, lymph nodes, and distant metastases at 1 h after injection, with an SUV of more than 10. The effective dose per a 100-MBq administered activity of F-FAPI-74 was 1.4 ± 0.2 mSv, and for Ga-FAPI-74 it was 1.6 mSv. Thus, the radiation burden of a diagnostic F-FAPI-74 PET scan is even lower than that of PET scans with F-FDG and other F tracers; Ga-FAPI-74 is comparable to other Ga ligands. FAPI PET/CT supported target volume definition for guiding radiotherapy. The high contrast and low radiation burden of FAPI-74 PET/CT favor multiple clinical applications. Centralized large-scale production of F-FAPI-74 or decentralized cold-kit labeling of Ga-FAPI-74 allows flexible routine use.
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http://dx.doi.org/10.2967/jnumed.120.245084DOI Listing
February 2021

Dataset of voxelwise correlated signal values of ADC, rCBV and FAP-specific PET of 13 Glioblastoma patients.

Data Brief 2020 Aug 15;31:105712. Epub 2020 May 15.

Division of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

This dataset is based on multimodal MRI and FAP-specific PET/CT Imaging applied to 13 patients with histologically proven glioblastomas. Imaging Data was processed using Medical Imaging Interaction Toolkit (MITK) software. MRI images (contrast enhanced T1w, T2w/FLAIR, ADC, rCBV) were co-registrated with FAP-specific PET images. T2w/FLAIR hyperintensities and contrast enhancing lesions were segmented manually. Necrotic areas were segmented manually and subtracted from T2w/FLAIR hyperintensities and contrast enhancing lesions. Voxelwise ADC/rCBV and PET signal intensities in projection on T2w/FLAIR hyperintensities and contrast enhancing lesions were extracted using the pixel dumper function of the MITK software and stored as excel-files. The data presented in this article has been analysed and described in the article FAP-specific "PET signaling shows a moderately positive correlation with relative CBV and no correlation with ADC in 13 IDH wildtype Glioblastomas" published in the European Journal of Radiology.
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http://dx.doi.org/10.1016/j.dib.2020.105712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256298PMC
August 2020

Vancomycin-Lipopeptide Conjugates with High Antimicrobial Activity on Vancomycin-Resistant Enterococci.

Pharmaceuticals (Basel) 2020 May 29;13(6). Epub 2020 May 29.

Department of Nuclear Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.

Multidrug-resistant bacteria represent one of the most important health care problems worldwide. While there are numerous drugs available for standard therapy, there are only a few compounds capable of serving as a last resort for severe infections. Therefore, approaches to control multidrug-resistant bacteria must be implemented. Here, a strategy of reactivating the established glycopeptide antibiotic vancomycin by structural modification with polycationic peptides and subsequent fatty acid conjugation to overcome the resistance of multidrug-resistant bacteria was followed. This study especially focuses on the structure-activity relationship, depending on the modification site and fatty acid chain length. The synthesized conjugates showed high antimicrobial potential on vancomycin-resistant enterococci. We were able to demonstrate that the antimicrobial activity of the vancomycin-lipopeptide conjugates depends on the chain length of the attached fatty acid. All conjugates showed good cytocompatibility in vitro and in vivo. Radiolabeling enabled the in vivo determination of pharmacokinetics in Wistar rats by molecular imaging and biodistribution studies. An improved biodistribution profile in comparison to unmodified vancomycin was observed. While vancomycin is rapidly excreted by the kidneys, the most potent conjugate shows a hepatobiliary excretion profile. In conclusion, these results demonstrate the potential of the structural modification of already established antibiotics to provide highly active compounds for tackling multidrug-resistant bacteria.
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http://dx.doi.org/10.3390/ph13060110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345083PMC
May 2020

First patient exceeding 5-year complete remission after Ac-PSMA-TAT.

Eur J Nucl Med Mol Imaging 2021 Jan 28;48(1):311-312. Epub 2020 May 28.

European Commission, Joint Research Centre, Directorate for Nuclear Safety and Security, Karlsruhe, Germany.

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http://dx.doi.org/10.1007/s00259-020-04875-yDOI Listing
January 2021

Clinical outcome of PSMA-guided radiotherapy for patients with oligorecurrent prostate cancer.

Eur J Nucl Med Mol Imaging 2021 Jan 13;48(1):143-151. Epub 2020 May 13.

Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.

Purpose: First-line treatment of patients with recurrent, metastatic prostate cancer involves hormone therapy with or without additional systemic therapies. Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) allows the detection of oligometastatic disease that may be amenable to image-guided radiotherapy. The current study classifies the type and localization of metastases and the clinical outcome of PSMA-PET/CT-guided radiotherapy to selected metastases.

Materials And Methods: Between 2011 and 2019, 86 patients with recurrent, oligometastatic prostate carcinoma were identified by PSMA-PET/CT and were treated with image-guided radiotherapy of their metastases. Sites of relapse were characterized, and the primary endpoint overall survival (OS), biochemical progression-free survival (bPFS), and androgen deprivation therapy (ADT)-free survival were tabulated.

Results: In total, 37% of the metastases were bone metastases, 48% were pelvic nodal metastases, and 15% were nodal metastases outside of the pelvis. After PSMA-guided radiotherapy, a biochemical response was detected in 83% of the cohort. A statistically significant decrease in the standard uptake value (SUV) was seen in irradiated metastases. After a median follow-up of 26 months, the 3-year OS and bPFS were 84% and 55%, respectively. The median time of ADT-free survival was 13.5 months. A better clinical outcome was observed for patients receiving concomitant ADT or more than 24 fractions of radiation.

Conclusion: PSMA-guided radiotherapy is a promising therapeutic approach with excellent infield control for men with oligorecurrent prostate carcinoma. However, prospective, randomized trials are necessary to determine if this approach confers a survival advantage.
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http://dx.doi.org/10.1007/s00259-020-04777-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835298PMC
January 2021

Interim PET Evaluation in Diffuse Large B-Cell Lymphoma Using Published Recommendations: Comparison of the Deauville 5-Point Scale and the ΔSUV Method.

J Nucl Med 2021 01 8;62(1):37-42. Epub 2020 May 8.

Klinik für Hämatologie, Universitätsklinikum, Essen, Germany.

The value of interim F-FDG PET/CT (iPET)-guided treatment decisions in patients with diffuse large B-cell lymphoma (DLBCL) has been the subject of much debate. This investigation focuses on a comparison of the Deauville score and the change-in-SUV (ΔSUV) approach-2 methods to assess early metabolic response to standard chemotherapy in DLBCL. Of 609 DLBCL patients participating in the PET-Guided Therapy of Aggressive Non-Hodgkin Lymphomas trial, iPET scans of 596 patients originally evaluated using the ΔSUV method were available for post hoc assessment of the Deauville score. A commonly used definition of an unfavorable iPET result according to the Deauville score is an uptake greater than that of the liver, whereas an unfavorable iPET scan with regard to the ΔSUV approach is characterized as a relative reduction of the SUV between baseline and iPET staging of less than or equal to 66%. We investigated the 2 methods' correlation and concordance by Spearman rank correlation coefficient and the agreement in classification, respectively. We further used Kaplan-Meier curves and Cox regression to assess differences in survival between patient subgroups defined by the prespecified cutoffs. Time-dependent receiver-operating-characteristic curve analysis provided information on the methods' respective discrimination performance. Deauville score and ΔSUV approach differed in their iPET-based prognosis. The ΔSUV approach outperformed the Deauville score in terms of discrimination performance-most likely because of a high number of false-positive decisions by the Deauville score. Cutoff-independent discrimination performance remained low for both methods, but cutoff-related analyses showed promising results. Both favored the ΔSUV approach, for example, for the segregation by iPET response, where the event-free survival hazard ratio was 3.14 (95% confidence interval, 2.22-4.46) for ΔSUV and 1.70 (95% confidence interval, 1.29-2.24) for the Deauville score. When considering treatment intensification, the currently used Deauville score cutoff of an uptake above that of the liver seems to be inappropriate and associated with potential harm for DLBCL patients. The ΔSUV criterion of a relative reduction in SUV of less than or equal to 66% should be considered as an alternative.
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http://dx.doi.org/10.2967/jnumed.120.244145DOI Listing
January 2021

FAP-specific PET signaling shows a moderately positive correlation with relative CBV and no correlation with ADC in 13 IDH wildtype glioblastomas.

Eur J Radiol 2020 Jun 20;127:109021. Epub 2020 Apr 20.

Division of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Objectives: Targeting Fibroblast Activation Protein (FAP) is a new approach for glioblastoma imaging. In a recent pilot study glioblastomas showed elevated tracer uptake with high intratumoral heterogeneity in projection on the corresponding T2w/FLAIR and contrast enhanced MRI lesions. In this study, we correlated FAP-specific signaling with apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) signals in MRI to further characterize the significance of FAP uptake.

Methods: Clinical PET/CT scans of 13 glioblastoma patients were performed post i. v. administration of Ga-labelled-FAP-specific tracer molecules. PET- and corresponding MRI-scans were co-registrated. 3d volumetric segmentations were performed of T2w/FLAIR lesions and contrast enhancing lesions within co-registrated MRI slides. Signal intensity values of FAP-specific PET signaling, ADC and rCBV were analyzed for their pixel wise correlation in each patient. Pooled estimates of the correlation coefficients were calculated by using the Fisher z-transformation.

Results: FAP-specific PET signals showed a moderately positive correlation with rCBV values which is more pronounced within the T2w/FLAIR lesion (pooled correlation 0,229) than in the contrast enhancing tumor region (pooled correlation 0.09). FAP-specific PET signals showed no correlation with ADC values.

Conclusions: The moderately positive correlation of FAP-specific signals with rCBV values in MRI indicates that FAP-signaling is not independent from perfusion, but also does not only reflect intratumoral perfusion differences. The missing correlation of FAP-specific signals with ADC indicates that FAP-specific imaging does not reflect cell density, but the spot-like expression of FAP in glioblastomas. The clinical value of FAP-specific imaging needs further investigation.
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http://dx.doi.org/10.1016/j.ejrad.2020.109021DOI Listing
June 2020

High prevalence of DNA damage repair gene defects and TP53 alterations in men with treatment-naïve metastatic prostate cancer -Results from a prospective pilot study using a 37 gene panel.

Urol Oncol 2020 07 10;38(7):637.e17-637.e27. Epub 2020 Apr 10.

Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.

Background: Defects in DNA damage repair genes characterize a subset of men with prostate cancer and provide an attractive opportunity for precision oncology approaches. The prevalence of such perturbations in newly diagnosed, treatment-naïve patients with a high risk for lethal disease outcome, however, has not been sufficiently explored.

Patients And Methods: Prostate cancer specimens from 67 men with newly diagnosed early onset, localized high-risk/locally advanced or metastatic prostate cancer were included in this prospective pilot study. Tumor samples, including 30 prostate biopsies, were analyzed by targeted next generation sequencing using a formalin-fixed, paraffin-embedded tissue-optimized 37 DNA damage repair and checkpoint gene panel.

Results: The drop-out rate due to an insufficient quantity of DNA was 4.5% (3 of 67 patients). In the remaining 64 patients, the rate of pathogenic DNA damage repair gene mutations was 26.6%. The highest rate of pathogenic DNA damage repair and checkpoint gene mutations was found in men with treatment-naïve metastatic prostate cancer (38.9%). In addition, a high number of likely pathogenic mutations and gene deletions were detected. Altogether, one or more pathogenic mutation, likely pathogenic mutation or gene deletion affected 43 of 64 patients (67.2%) including 29 of 36 patients (80.6%) with treatment-naïve metastatic prostate cancer. Men with metastatic prostate cancer showed a high prevalence of alterations in TP53 (36.1%).

Conclusions: This pilot study demonstrates the feasibility, performance and clinical relevance of somatic targeted next generation sequencing using a unique 37 DNA damage repair and checkpoint gene panel under routine conditions. Our results indicate that this approach can detect actionable DNA repair gene alterations, uncommon mutations as well as mutations associated with therapy resistance in a high number of patients, in particular patients with treatment-naïve metastatic prostate cancer.
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http://dx.doi.org/10.1016/j.urolonc.2020.03.001DOI Listing
July 2020

Vancomycin Resistance Is Overcome by Conjugation of Polycationic Peptides.

Angew Chem Int Ed Engl 2020 06 21;59(23):8823-8827. Epub 2020 Apr 21.

Department of Nuclear Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Multidrug-resistant bacteria represent one of the biggest challenges facing modern medicine. The increasing prevalence of glycopeptide resistance compromises the efficacy of vancomycin, for a long time considered as the last resort for the treatment of resistant bacteria. To reestablish its activity, polycationic peptides were conjugated to vancomycin. By site-specific conjugation, derivatives that bear the peptide moiety at four different sites of the antibiotic were synthesized. The most potent compounds exhibited an approximately 1000-fold increased antimicrobial activity and were able to overcome the most important types of vancomycin resistance. Additional blocking experiments using d-Ala-d-Ala revealed a mode of action beyond inhibition of cell-wall formation. The antimicrobial potential of the lead candidate FU002 for bacterial infection treatments could be demonstrated in an in vivo study. Molecular imaging and biodistribution studies revealed that conjugation engenders superior pharmacokinetics.
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http://dx.doi.org/10.1002/anie.202002727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323874PMC
June 2020

Improving antibody-based therapies by chemical engineering of antibodies with multimeric cell-penetrating peptides for elevated intracellular delivery.

J Control Release 2020 06 14;322:200-208. Epub 2020 Mar 14.

Department of Nuclear Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. Electronic address:

Monoclonal antibodies (mAbs) are increasingly exploited as vehicles for the targeted delivery of cytotoxic drugs. In antibody-drug conjugates (ADCs) antibodies specifically deliver cytotoxic compounds to cancer cells. Here, we present a technology for elevating the intracellular delivery of antibodies by the conjugation of tetrameric cell-penetrating peptides (tCPPs). The solid phase synthesis of tCPPs and their application in a chemical modification strategy for mAbs provides constructs that attain up to fourfold elevated internalization rates while retaining the mAbs target specificity. The antigen independent internalization is accompanied by beneficial pharmacokinetics limiting off-target accumulation. Applicability was proven for matuzumab, trastuzumab and the ADC Kadcyla®. Cytotoxicity studies of tCPP-conjugates of Kadcyla® resulted in a sixfold increased cytotoxicity proving the potential of chemical modification strategies to extend the applicability of biologicals. This constitutes a significant step towards next-generation antibody-based therapeutics.
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http://dx.doi.org/10.1016/j.jconrel.2020.03.005DOI Listing
June 2020

Ac-PSMA-617 for Therapy of Prostate Cancer.

Semin Nucl Med 2020 03 14;50(2):133-140. Epub 2020 Feb 14.

Department of Nuclear Medicine, University Hospital Heidelberg, Germany.

Prostate-specific membrane antigen (PSMA)-targeting radio-ligand therapy with beta-emitting Lutetium has already been investigated in several early phase dosimetry studies, demonstrated promising results in phase-2, and recently the first phase-3 trial finished recruitment. In contrast, PSMA-targeting alpha-particle therapy (TAT) has only been evaluated in few preclinical experiments, preliminary dosimetry attempts and some retrospective observational studies, yet. First clinical experience with Ac-PSMA-617 demonstrates promising antitumor activity with a 63%-70% PSA-response rate, 10-15 months duration of response and complete remissions in approximately ten percent of patients, some of them with enduring relapse-free survival. Nevertheless, without comparative trials there is no prove whether, applied in identical clinical situations, Ac-PSMA-617 is really more efficiently than Lu-PSMA-617 or vice versa. However, there is some good rationale, that PSMA-TAT might have advantages in particular clinical indications. This includes patients with diffuse type red-marrow infiltration by reducing off-target radiation to surrounding cells; ablation of micrometastases after favorable response to other previous therapy or someday in early stage disease. Also treatment escalation of patients, either with poor response to Lu-PSMA or harboring adverse prognostic biomarkers, appears promising. In preclinical research, alpha-radiation demonstrated stronger induction of abscopal effects than beta-radiation; favoring its usage as a combination partner with immunotherapies. So, further evaluation of PSMA-TAT is definitely warranted. Recently, de-escalated treatment protocols and application of Ac/Lu-PSMA "cocktail"-regimens improved the tolerability of Ac-PSMA-617 TAT, reducing the risk for development dry-mouth syndrome. This opens new avenues for future application in earlier stage disease.
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http://dx.doi.org/10.1053/j.semnuclmed.2020.02.004DOI Listing
March 2020

Design and Development of Tc-Labeled FAPI Tracers for SPECT Imaging and Re Therapy.

J Nucl Med 2020 10 13;61(10):1507-1513. Epub 2020 Mar 13.

Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg Germany

Most epithelial tumors recruit fibroblasts and other nonmalignant cells and activate them into cancer-associated fibroblasts. This often leads to overexpression of the membrane serine protease fibroblast-activating protein (FAP). It has already been shown that DOTA-bearing FAP inhibitors (FAPIs) generate high-contrast images with PET/CT scans. Since SPECT is a lower-cost and more widely available alternative to PET, Tc-labeled FAPIs represent attractive tracers for imaging applications in a larger number of patients. Furthermore, the chemically homologous nuclide Re is available from generators, which allows FAP-targeted endoradiotherapy. For the preparation of Tc-tricarbonyl complexes, a chelator was selected whose carboxylic acids can easily be converted into various derivatives in the finished product, enabling a platform strategy based on the original tracer. The obtained Tc complexes were investigated in vitro by binding and competition experiments on FAP-transfected HT-1080 (HT-1080-FAP) or on mouse FAP-expressing (HEK-muFAP) and CD26-expressing (HEKCD26) HEK cells and characterized by planar scintigraphy and organ distribution studies in tumor-bearing mice. Furthermore, a first-in-humans application was done on 2 patients with ovarian and pancreatic cancer, respectively. Tc-FAPI-19 showed specific binding to recombinant FAP-expressing cells with high affinity. Unfortunately, liver accumulation, biliary excretion, and no tumor uptake were observed on planar scintigraphy for a HT-1080-FAP-xenotransplanted mouse. To improve the pharmacokinetic properties, hydrophilic amino acids were attached to the chelator moiety of the compound. The resulting Tc-labeled FAPI tracers revealed excellent binding properties (≤45% binding; >95% internalization), high affinity (half-maximal inhibitory concentration, 6.4-12.7 nM), and significant tumor uptake (≤5.4% injected dose per gram of tissue) in biodistribution studies. The lead candidate Tc-FAPI-34 was applied for diagnostic scintigraphy and SPECT of patients with metastasized ovarian and pancreatic cancer for follow-up to therapy with Y-FAPI-46. Tc-FAPI-34 accumulated in the tumor lesions, as also shown on PET/CT imaging using Ga-FAPI-46. Tc-FAPI-34 represents a powerful tracer for diagnostic scintigraphy, especially when PET imaging is not available. Additionally, the chelator used in this compound allows labeling with the therapeutic nuclide Re, which is planned for the near future.
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http://dx.doi.org/10.2967/jnumed.119.239731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539653PMC
October 2020

Baseline and interim PET-based outcome prediction in peripheral T-cell lymphoma: A subgroup analysis of the PETAL trial.

Hematol Oncol 2020 Aug 18;38(3):244-256. Epub 2020 Feb 18.

Klinik für Gastroenterologie, Hämatologie und internistische Onkologie und Endokrinologie, Klinikum Dortmund, Germany.

The prospective randomized Positron Emission Tomography (PET)-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial was designed to test the ability of interim PET (iPET) to direct therapy. As reported previously, outcome remained unaffected by iPET-based treatment changes. In this subgroup analysis, we studied the prognostic value of baseline total metabolic tumor volume (TMTV) and iPET response in 76 patients with T-cell lymphoma. TMTV was measured using the 41% maximum standardized uptake value (SUV ) and SUV thresholding methods. Interim PET was performed after two treatment cycles and evaluated using the ΔSUV approach and the Deauville scale. Because of significant differences in outcome, patients with anaplastic lymphoma kinase (ALK)-positive lymphoma were analyzed separately from patients with ALK-negative lymphoma. In the latter, TMTV was statistically significantly correlated with progression-free survival, with thresholds best dichotomizing the population, of 232 cm using SUV and 460 cm using SUV . For iPET response, the respective thresholds were 46.9% SUV reduction and Deauville score 1-4 vs 5. The proportion of poor prognosis patients was 46% and 29% for TMTV by SUV and SUV , and 29% and 25% for iPET response by ΔSUV and Deauville, respectively. At diagnosis, the hazard ratio (95% confidence interval) for poor prognosis vs good prognosis patients according to TMTV was 2.291 (1.135-4.624) for SUV and 3.206 (1.524-6.743) for SUV . At iPET, it was 3.910 (1.891-8.087) for ΔSUV and 4.371 (2.079-9.187) for Deauville. On multivariable analysis, only TMTV and iPET response independently predicted survival. Patients with high baseline TMTV and poor iPET response (22% of the population) invariably progressed or died within the first year (hazard ratio, 9.031 [3.651-22.336]). Due to small numbers and events, PET did not predict survival in ALK-positive lymphoma. Baseline TMTV and iPET response are promising tools to select patients with ALK-negative T-cell lymphoma for early allogeneic transplantation or innovative therapies.
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http://dx.doi.org/10.1002/hon.2697DOI Listing
August 2020

The Role of Ga-FAPI PET/CT for Patients with Malignancies of the Lower Gastrointestinal Tract: First Clinical Experience.

J Nucl Med 2020 09 14;61(9):1331-1336. Epub 2020 Feb 14.

Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany

For oncologic management or radiotherapy planning, reliable staging tools are essential. The recent development of quinoline-based ligands targeting cancer-associated fibroblasts demonstrated promising preclinical and clinical results. The current study aimed to evaluate the role of fibroblast activation protein inhibitor (FAPI) PET/CT as a first clinical analysis for primary malignancies within the lower gastrointestinal tract (LGT). Ga-FAPI PET/CT was performed on a cohort of 22 patients with LGT tumors, including 15 patients with metastatic disease, 1 patient with suspected local relapse, and 6 treatment-naïve patients. Uptake of Ga-FAPI-04 and Ga-FAPI-46 was quantified by SUV and SUV After comparison with standard imaging, changes in tumor stage or localization and in oncologic or radiooncologic management were recorded. The highest uptake of FAPI tracer was observed in liver metastases and anal cancer, with an SUV of 9.1 and 13.9, respectively. Because of low background activity in normal tissue, there was a high tumor-to-background ratio of more than 3 in most lesions. In treatment-naïve patients, TNM was changed in 50%, whereas in patients with metastases, new findings occurred in 47%. In total, FAPI imaging caused a high, medium, and low change in oncologic or radiooncologic management in 19%, 33%, and 29%, respectively. For almost every patient undergoing irradiation, target volume delineation was improved by Ga-FAPI PET/CT. The present study demonstrated that both primary and metastatic LGT tumors were reliably detected by Ga-FAPI PET/CT, leading to relevant changes in TNM status and oncologic or radiooncologic management. Ga-FAPI PET/CT seems to be a highly promising imaging agent for the diagnosis and management of LGT tumors, potentially opening new applications for tumor staging or restaging.
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http://dx.doi.org/10.2967/jnumed.119.237016DOI Listing
September 2020

Radiation Dosimetry and Biodistribution of Ga-FAPI-46 PET Imaging in Cancer Patients.

J Nucl Med 2020 08 13;61(8):1171-1177. Epub 2019 Dec 13.

Physics and Biology in Medicine Interdepartmental Graduate Program, David Geffen School of Medicine, UCLA, Los Angeles, California

Targeting cancer-associated fibroblasts (CAFs) has become an attractive goal for diagnostic imaging and therapy because they can constitute as much as 90% of a tumor mass. The serine protease fibroblast activation protein (FAP) is overexpressed selectively in CAFs, drawing interest in FAP as a stromal target. The quinoline-based FAP inhibitor (FAPI) PET tracer Ga-FAPI-04 has been previously shown to yield high tumor-to-background ratios (TBRs) in patients with various cancers. Recent developments toward an improved compound for therapeutic application have identified FAPI-46 as a promising agent because of an increased tumor retention time in comparison with FAPI-04. Here, we present a PET biodistribution and radiation dosimetry study of Ga-FAPI-46 in cancer patients. Six patients with different cancers underwent serial Ga-FAPI-46 PET/CT scans at 3 time points after radiotracer injection: 10 min, 1 h, and 3 h. The source organs consisted of the kidneys, bladder, liver, heart, spleen, bone marrow, uterus, and remainder of body. OLINDA/EXM software, version 1.1, was used to fit and integrate the kinetic organ activity data to yield total-body and organ time-integrated activity coefficients and residence times and, finally, organ-absorbed doses. SUVs and TBR were generated from the contoured tumor and source-organ volumes. Spheric volumes in muscle and blood pool were also obtained for TBR (tumor SUV/organ SUV). At all time points, average SUV was highest in the liver. Tumor and organ SUV decreased over time, whereas TBRs in all organs but the uterus increased. The organs with the highest effective doses were bladder wall (2.41E-03 mSv/MBq), followed by ovaries (1.15E-03 mSv/MBq) and red marrow (8.49E-04 mSv/MBq). The average effective total-body dose was 7.80E-03 mSv/MBq. Ga-FAPI-46 PET/CT has a favorable dosimetry profile, with an estimated whole-body dose of 5.3 mSv for an administration of 200 MBq (5.4 mCi) of Ga-FAPI-46 (1.56 ± 0.26 mSv from the PET tracer and 3.7 mSv from 1 low-dose CT scan). The biodistribution study showed high TBRs increasing over time, suggesting high diagnostic performance and favorable tracer kinetics for potential therapeutic applications.
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http://dx.doi.org/10.2967/jnumed.119.236786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413240PMC
August 2020

Positive FAPI-PET/CT in a metastatic castration-resistant prostate cancer patient with PSMA-negative/FDG-positive disease.

Eur J Nucl Med Mol Imaging 2020 07 9;47(8):2040-2041. Epub 2019 Dec 9.

Department of Nuclear Medicine, Saarland University Hospital, Kirrberger Str., Geb. 50, D-66421, Homburg, Germany.

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http://dx.doi.org/10.1007/s00259-019-04623-xDOI Listing
July 2020

Mapping Prostate Cancer Lesions Before and After Unsuccessful Salvage Lymph Node Dissection Using Repeat PSMA PET.

J Nucl Med 2020 07 5;61(7):1037-1042. Epub 2019 Dec 5.

Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK), University Hospital Essen, Essen, Germany

The aim of this study was to analyze patterns of persistent versus recurrent or new PET lesions in a selected patient cohort with prostate-specific antigen (PSA) persistence after salvage lymph node dissection (SLND) and pre-procedure and post-procedure prostate-specific membrane antigen (PSMA) ligand PET. Sixteen patients were included in this multicenter study. The inclusion criteria were PSMA PET performed for biochemical recurrence before SLND (pre-SLND PET) and repeat PSMA PET performed for a persistently elevated PSA level (≥0.1 ng/mL) at least 6 wk after SLND (post-SLND PET). Image analysis was performed by 3 independent nuclear medicine physicians applying the molecular imaging TNM system PROMISE. Lesions were confirmed by histopathology, presence on correlative CT/MRI/bone scanning, or PSA response after focal therapy. Post-SLND PET identified prostate cancer lesions in 88% (14/16) of patients with PSA persistence after SLND. Median PSA was 1.2 ng/mL (interquartile range, 0.6-2.8 ng/mL). Disease was confined to the pelvis in 56% of patients (9/16), and most of these men had common iliac (6/16, 38%) and internal iliac lymph node metastases (6/16, 38%). Extrapelvic disease was detected in 31% of patients (5/16). In pre- and post-SLND PET comparison, 10 of 16 had at least one lesion already detected at baseline (63% PET persistence), 4 of 16 had new lesions only (25% PET recurrence), and 2 had no disease on post-SLND PET. All validated regions (11 regions in 9 patients) were true-positive. Nine of 14 (64%) patients underwent repeat local therapies after SLND (7/14 radiotherapy, 2/14 surgery). SLND of pelvic nodal metastases was often not complete according to PSMA PET. About two thirds of patients had PET-positive nodal disease after SLND already seen on pre-SLND PSMA PET. Notably, about one quarter of patients had new lesions, not detected by presurgical PSMA PET.
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http://dx.doi.org/10.2967/jnumed.119.235374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383079PMC
July 2020

A Conversation Between Uwe Haberkorn and Johannes Czernin.

J Nucl Med 2019 Nov;60(11):1495-1498

David Geffen School of Medicine at UCLA, Los Angeles, California.

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http://dx.doi.org/10.2967/jnumed.119.236760DOI Listing
November 2019

Ga-PSMA-11 PET/CT in patients with recurrent prostate cancer-a modified protocol compared with the common protocol.

Eur J Nucl Med Mol Imaging 2020 03 1;47(3):624-631. Epub 2019 Nov 1.

Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Purpose: Ga-PSMA-11 PET/CT is commonly performed at 1 h post injection (p.i.). However, various publications have demonstrated that most prostate cancer (PC) lesions exhibit higher contrast at later imaging. The aim of this study was to compare the "common" protocol of Ga-PSMA-11 PET/CT with a modified protocol.

Methods: In 2017, we used the following scanning protocol for Ga-PSMA-11 PET/CT in patients with recurrent PC: acquisition at 1 h p.i. without further preparations. From 2018, all scans were conducted at 1.5 h p.i. In addition, patients were orally hydrated with 1 L of water 0.5 h p.i. and were injected with 20 mg of furosemide 1 h p.i. Both protocols including 112 patients (2017) and 156 (modified protocol in 2018) were retrospectively compared. Rates of pathologic scans, maximum standardized uptake values (SUVmax), and tumor contrast (ratio lesion-SUVmax/background-SUVmean) as well as average standardized uptake values (SUVmean) of urinary bladder were analyzed.

Results: Both tumor contrast and tracer uptake were significantly (p < 0.001) higher in the novel protocol. Although statistically not significant, the rates of pathologic scans were also higher in the modified protocol: 76.3% vs. 68.8% for all PSA values including 38.9% vs. 25.0% for PSA < 0.5 ng/ml and 60.0% vs. 56.7% for PSA > 0.5-≤ 2.0 ng/ml. Average SUVmean of the urinary bladder was significantly (p < 0.001) lower with the modified protocol.

Conclusions: The modified protocol, which includes a combination of delayed image acquisition at 1.5 h p.i., hydration, and furosemide resulted in higher tumor contrast and seems to have the potential to increase the rates of pathological scans, especially at low PSA levels.
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http://dx.doi.org/10.1007/s00259-019-04548-5DOI Listing
March 2020

Targeting of activated fibroblasts for imaging and therapy.

EJNMMI Radiopharm Chem 2019 Jul 25;4(1):16. Epub 2019 Jul 25.

Department of Nuclear Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Tumors form a complex environment consisting of a variety of non-malignant cells. Especially cancer-associated fibroblasts have been shown to have an important role for different aspects of malignant tumors such as migration, metastasis, resistance to chemotherapy and immunosuppression. Therefore, a targeting of these cells may be useful for both imaging and therapy. In this respect, an interesting target is the fibroblast activation protein (FAP) which is expressed in activated fibroblasts, but not in quiescent fibroblasts, giving the opportunity to use this membrane-anchored enzyme as a target for radionuclide-based approaches for diagnosis and treatment of tumors and for the diagnosis of non-malignant disease associated with a remodelling of the extracellular matrix.
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http://dx.doi.org/10.1186/s41181-019-0069-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658625PMC
July 2019

Response Prediction of Lu-PSMA-617 Radioligand Therapy Using Prostate-Specific Antigen, Chromogranin A, and Lactate Dehydrogenase.

J Nucl Med 2020 05 25;61(5):689-695. Epub 2019 Oct 25.

Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Neuroendocrinelike transdifferentiation of prostate cancer adenocarcinomas correlates with serum levels of chromogranin A (CgA) and drives treatment resistance. The aim of this work was to evaluate whether CgA can serve as a response predictor for Lu-prostate-specific membrane antigen 617 (PSMA) radioligand therapy (RLT) in comparison with the established tumor markers. One hundred consecutive patients with metastasized castration-resistant prostate cancer scheduled for PSMA RLT were evaluated for prostate-specific antigen (PSA), lactate dehydrogenase (LDH), and CgA at baseline and in follow-up of PSMA RLT. Tumor uptake of PSMA ligand, a known predictive marker for response, was assessed as a control variable. From the 100 evaluated patients, 35 had partial remission, 16 stable disease, 15 mixed response, and 36 progression of disease. Tumor uptake above salivary gland uptake translated into partial remission, with an odds ratio (OR) of 60.265 (95% confidence interval [CI], 5.038-720.922). Elevated LDH implied a reduced chance for partial remission, with an OR of 0.094 (95% CI, 0.017-0.518), but increased the frequency of progressive disease (OR, 2.717; 95% CI, 1.391-5.304). All patients who achieved partial remission had a normal baseline LDH. Factor-2 elevation of CgA increased the risk for progression, with an OR of 3.089 (95% CI, 1.302-7.332). Baseline PSA had no prognostic value for response prediction. In our cohort, baseline PSA had no prognostic value for response prediction. LDH was the marker with the strongest prognostic value, and elevated LDH increased the risk for progression of disease under PSMA RLT. Elevated CgA demonstrated a moderate impact as a negative prognostic marker in general but was explicitly related to the presence of liver metastases. Well in line with the literature, sufficient tumor uptake is a prerequisite to achieve tumor response.
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http://dx.doi.org/10.2967/jnumed.119.231431DOI Listing
May 2020

Patients Resistant Against PSMA-Targeting α-Radiation Therapy Often Harbor Mutations in DNA Damage-Repair-Associated Genes.

J Nucl Med 2020 05 10;61(5):683-688. Epub 2019 Oct 10.

Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Prostate-specific membrane antigen (PSMA)-targeting α-radiation therapy (TAT) is an emerging treatment modality for metastatic castration-resistant prostate cancer. There is a subgroup of patients with poor response despite sufficient expression of PSMA in their tumors. The aim of this work was to characterize PSMA-TAT-nonresponding lesions by targeted next-generation sequencing. Of 60 patients treated with Ac-PSMA-617, we identified 10 patients who presented with a poor response despite sufficient tumor uptake in PSMA PET/CT. We were able to perform CT-guided biopsies with histologic validation of the nonresponding lesions in 7 of these nonresponding patients. Specimens were analyzed by targeted next-generation sequencing interrogating 37 DNA damage-repair-associated genes. In the 7 tumor samples analyzed, we found a total of 15 whole-gene deletions, deleterious or presumably deleterious mutations affecting ( = 3), ( = 2), ( = 2), and and ( = 1 each). The average number of deleterious or presumably deleterious mutations was 2.2 (range, 0-6) per patient. In addition, several variants of unknown significance in and various genes were detected. Patients with resistance to PSMA-TAT despite PSMA positivity frequently harbor mutations in DNA damage-repair and checkpoint genes. Although the causal role of these alterations in the patient outcome remains to be determined, our findings encourage future studies combining PSMA-TAT and DNA damage-repair-targeting agents such as poly(ADP-ribose)-polymerase inhibitors.
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http://dx.doi.org/10.2967/jnumed.119.234559DOI Listing
May 2020

Theranostics Targeting Fibroblast Activation Protein in the Tumor Stroma: Cu- and Ac-Labeled FAPI-04 in Pancreatic Cancer Xenograft Mouse Models.

J Nucl Med 2020 04 4;61(4):563-569. Epub 2019 Oct 4.

Institute for Radiation Sciences, Osaka University, Osaka, Japan.

Fibroblast activation protein (FAP), which promotes tumor growth and progression, is overexpressed in cancer-associated fibroblasts of many human epithelial cancers. Because of its low expression in normal organs, FAP is an excellent target for theranostics. In this study, we used radionuclides with relatively long half-lives, Cu (half-life, 12.7 h) and Ac (half-life, 10 d), to label FAP inhibitors (FAPIs) in mice with human pancreatic cancer xenografts. Male nude mice (body weight, 22.5 ± 1.2 g) were subcutaneously injected with human pancreatic cancer cells (PANC-1, = 12; MIA PaCa-2, = 8). Tumor xenograft mice were investigated after the intravenous injection of Cu-FAPI-04 (7.21 ± 0.46 MBq) by dynamic and delayed PET scans (2.5 h after injection). Static scans 1 h after the injection of Ga-FAPI-04 (3.6 ± 1.4 MBq) were also acquired for comparisons using the same cohort of mice ( = 8). Immunohistochemical staining was performed to confirm FAP expression in tumor xenografts using an FAP-α-antibody. For radioligand therapy, Ac-FAPI-04 (34 kBq) was injected into PANC-1 xenograft mice ( = 6). Tumor size was monitored and compared with that of control mice ( = 6). Dynamic imaging of Cu-FAPI-04 showed rapid clearance through the kidneys and slow washout from tumors. Delayed PET imaging of Cu-FAPI-04 showed mild uptake in tumors and relatively high uptake in the liver and intestine. Accumulation levels in the tumor or normal organs were significantly higher for Cu-FAPI-04 than for Ga-FAPI-04, except in the heart, and excretion in the urine was higher for Ga-FAPI-04 than for Cu-FAPI-04. Immunohistochemical staining revealed abundant FAP expression in the stroma of xenografts. Ac-FAPI-04 injection showed significant tumor growth suppression in the PANC-1 xenograft mice, compared with the control mice, without a significant change in body weight. This proof-of-concept study showed that Cu-FAPI-04 and Ac-FAPI-04 could be used in theranostics for the treatment of FAP-expressing pancreatic cancer. α-therapy targeting FAP in the cancer stroma is effective and will contribute to the development of a new treatment strategy.
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http://dx.doi.org/10.2967/jnumed.119.233122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198371PMC
April 2020

Development of Novel PSMA Ligands for Imaging and Therapy with Copper Isotopes.

J Nucl Med 2020 01 20;61(1):70-79. Epub 2019 Sep 20.

Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany

Prostate-specific membrane antigen (PSMA)-binding tracers have been shown to be promising agents for the specific targeting of prostate tumors. On labeling with the short-lived isotopes F and Ga, excellent molecular imaging performance is achieved. This potential could be further exploited using long-lived isotopes. Because of the favorable half-life of Cu, tracers labeled with this PET nuclide could solve logistic problems. Moreover, this isotope provides a theranostic pair with the therapeutic copper isotope Cu. Hence, 9 novel tracers that combine dedicated copper chelators with the PSMA-specific urea-based binding motif were developed. The precursors were obtained by solid-phase synthesis. The purity and molecular weight of the PSMA ligands were confirmed by high-performance liquid chromatography and liquid chromatography-mass spectrometry. The compounds were labeled with Cu, with a radiolabeling yield of more than 99%. Competitive cell binding assays and internalization assays were performed with C4-2 cells, a subline of the PSMA-positive cell line LNCaP (human lymph node carcinoma of the prostate). In vitro serum stability, the stability of Cu-CA003 in blood, and the in vivo fate of neat Cu-chloride or Cu-CA003 were determined to prove whether the stability of the radiolabeled compounds is sufficient to ensure no significant loss of copper during the targeting process. For PET imaging and biodistribution studies, a C4-2 tumor-bearing mouse model was used. The radiolabeled Cu-PSMA ligands showed high serum stability. All PSMA ligands showed high inhibition potencies, with equilibrium inhibition constants in the low nanomolar range. Cu-CA003 and Cu-CA005 showed high internalization ratios (34.6% ± 2.8 and 18.6% ± 4.4, respectively). Both the in vitro serum stability determination and the in vivo characterization of the main radiolabeled compounds confirmed that, except for Cu-PSMA-617, all compounds showed high serum stability within the observation period of 24 h. Small-animal PET imaging demonstrated high tumor uptake within 20 min. Organ distribution studies confirmed high specific uptake in the tumor, with 30.8 ± 12.6 percentage injected dose (%ID)/g at 1 h after injection. Rapid clearance from the kidneys was observed-a decrease from 67.0 ± 20.9 %ID/g at 1 h after injection to 7.5 ± 8.51 %ID/g at 24 h after injection (in the case of CA003). The performance of CA003, the compound with the best preclinical properties, was assessed in a first patient. In line with its preclinical data, PET imaging resulted in clear visualization of the cancer lesions, with high contrast. The Cu-labeled PSMA ligands are promising agents to target PSMA and visualize PSMA-positive tumor lesions as shown in preclinical evaluation by small-animal PET studies, organ distribution, and a patient application. Most importantly, the images obtained at 20 h enabled delineation of unclear lesions, showing that the compounds fulfill the prerequisite for dosimetry in the course of therapy planning with Cu. Thus, we suggest clinical use of copper-labeled CA003 for diagnostics and radiotherapy of prostate cancer.
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http://dx.doi.org/10.2967/jnumed.119.229054DOI Listing
January 2020

Tc-Hydroxydiphosphonate quantification of extracellular matrix mineralization in 3D human mesenchymal stem cell cultures.

Bone Joint Res 2019 Jul 2;8(7):333-341. Epub 2019 Aug 2.

Department for Orthopaedics and Traumatology, Kepler University Hospital GmbH, Johannes Kepler University Linz, Austria.

Objectives: Bone tissue engineering is one of the fastest growing branches in modern bioscience. New methods are being developed to achieve higher grades of mineral deposition by osteogenically inducted mesenchymal stem cells. In addition to well established monolayer cell culture models, 3D cell cultures for stem cell-based osteogenic differentiation have become increasingly attractive to promote bone formation. One of the main problems of scaffold-based osteogenic cell cultures is the difficulty in quantifying the amount of newly produced extracellular mineral deposition, as a marker for new bone formation, without destroying the scaffold. In recent studies, we were able to show that Tc-methylene diphosphonate (Tc-MDP), a gamma radiation-emitting radionuclide, can successfully be applied as a reliable quantitative marker for mineral deposition as this tracer binds with high affinity to newly produced hydroxyapatite (HA).

Methods: Within the present study, we evaluated whether this promising new method, using Tc-hydroxydiphosphonate (Tc-HDP), can be used to quantify the amount of newly formed extracellular HA in a 3D cell culture model. Highly porous collagen type II scaffolds were seeded with 1 × 106 human mesenchymal stem cells (hMSCs; n = 6) and cultured for 21 days in osteogenic media (group A - osteogenic (OSM) group) and in parallel in standard media (group B - negative control (CNTRL) group). After incubation with Tc-HDP, the tracer uptake, reflected by the amount of emitted gamma counts, was measured.

Results: We saw a higher uptake (up to 15-fold) of the tracer in the OSM group A compared with the CNTRL group B. Statistical analysis of the results (Student`s -test) revealed a significantly higher amount of emitted gamma counts in the OSM group (p = 0.048). Qualitative and semi-quantitative analysis by Alizarin Red staining confirmed the presence of extracellular HA deposition in the OSM group.

Conclusion: Our data indicate that Tc-HDP labelling is a promising tool to track and quantify non-destructive local HA deposition in 3D stem cell cultures.: T. L. Grossner, U. Haberkorn, T. Gotterbarm. Tc-Hydroxydiphosphonate quantification of extracellular matrix mineralization in 3D human mesenchymal stem cell cultures. 2019;8:333-341. doi: 10.1302/2046-3758.87.BJR-2017-0248.R1.
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http://dx.doi.org/10.1302/2046-3758.87.BJR-2017-0248.R1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691365PMC
July 2019

EANM procedure guidelines for radionuclide therapy with Lu-labelled PSMA-ligands (Lu-PSMA-RLT).

Eur J Nucl Med Mol Imaging 2019 Nov 22;46(12):2536-2544. Epub 2019 Aug 22.

Department of Nuclear Medicine, |Universitätsklinikum Essen, Essen, Germany.

Prostate-specific membrane antigen (PSMA) is expressed in most prostate cancers and can be identified by PSMA-ligand imaging, which has already become clinically accepted in several countries in- and outside Europe. PSMA-directed radioligand therapy (PSMA-RLT) with Lutetium-177 (Lu-PSMA) is currently undergoing clinical validation. Retrospective observational data have documented favourable safety and striking clinical responses. Recent results from a prospective clinical trial (phase II) have been published confirming high response rates, low toxicity and reduction of pain in metastatic castration-resistant prostate cancer (mCRPC) patients who had progressed after conventional treatments. Such patients typically survive for periods less than 1.5 years. This has led some facilities to adopt compassionate or unproven use of this therapy, even in the absence of validation within a randomised-controlled trial. As a result, a consistent body of evidence exists to support efficacy and safety data of this treatment. The purpose of this guideline is to assist nuclear medicine specialists to deliver PSMA-RLT as an "unproven intervention in clinical practice", in accordance with the best currently available knowledge.
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http://dx.doi.org/10.1007/s00259-019-04485-3DOI Listing
November 2019

Molecular Imaging of Fibroblast Activity After Myocardial Infarction Using a Ga-Labeled Fibroblast Activation Protein Inhibitor, FAPI-04.

J Nucl Med 2019 12 12;60(12):1743-1749. Epub 2019 Aug 12.

Department of Nuclear Medicine, Klinikum rechts der Isar der TUM, Munich, Germany.

Heart failure remains a major source of late morbidity and mortality after myocardial infarction (MI). The temporospatial presence of activated fibroblasts in the injured myocardium predicts the quality of cardiac remodeling after MI. Therefore, monitoring of activated fibroblasts is of great interest for studying cardiac remodeling after MI. Fibroblast activation protein (FAP) expression is upregulated in activated fibroblasts. This study investigated the feasibility of imaging activated fibroblasts with a new Ga-labeled FAP inhibitor (Ga-FAPI-04) for PET imaging of fibroblast activation in a preclinical model of MI. MI and sham-operated rats were scanned with Ga-FAPI-04 PET/CT (1, 3, 6, 14, 23, and 30 d after MI) and with F-FDG (3 d after MI). Dynamic Ga-FAPI-04 PET and blocking studies were performed on MI rats 7 d after coronary ligation. After in vivo scans, the animals were euthanized and their hearts harvested for ex vivo analyses. Cryosections were prepared for autoradiography, hematoxylin and eosin (H&E), and immunofluorescence staining. Ga-FAPI-04 uptake in the injured myocardium peaked on day 6 after coronary ligation. The tracer accumulated intensely in the MI territory, as identified by decreased F-FDG uptake and confirmed by PET/MR and H&E staining. Autoradiography and H&E staining of cross-sections revealed that Ga-FAPI-04 accumulated mainly at the border zone of the infarcted myocardium. In contrast, there was only minimal uptake in the infarct of the blocked rats, comparable to the uptake in the remote noninfarcted myocardium (PET image-derived ratio of infarct uptake to remote uptake: 6 ± 2). Immunofluorescence staining confirmed the presence of FAP-positive myofibroblasts in the injured myocardium. Morphometric analysis of the whole-heart sections demonstrated 3- and 8-fold higher FAP-positive fibroblast density in the border zone than in the infarct center and remote area, respectively. Ga-FAPI-04 represents a promising radiotracer for in vivo imaging of post-MI fibroblast activation. Noninvasive imaging of activated fibroblasts may have significant diagnostic and prognostic value, which could aid clinical management of patients after MI.
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http://dx.doi.org/10.2967/jnumed.119.226993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894377PMC
December 2019

IDH-wildtype glioblastomas and grade III/IV IDH-mutant gliomas show elevated tracer uptake in fibroblast activation protein-specific PET/CT.

Eur J Nucl Med Mol Imaging 2019 Nov 6;46(12):2569-2580. Epub 2019 Aug 6.

Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.

Purpose: Targeting fibroblast activation protein (FAP) is a new diagnostic approach allowing the visualization of tumor stroma. Here, we applied FAP-specific PET imaging to gliomas. We analyzed the target affinity and specificity of two FAP ligands (FAPI-02 and FAPI-04) in vitro, and the pharmacokinetics and biodistribution in mice in vivo. Clinically, we used Ga-labeled FAPI-02/04 for PET imaging in 18 glioma patients (five IDH-mutant gliomas, 13 IDH-wildtype glioblastomas).

Methods: For binding studies with Lu-radiolabeled FAPI-02/04, we used the glioblastoma cell line U87MG, FAP-transfected fibrosarcoma cells, and CD26-transfected human embryonic kidney cells. For pharmacokinetic and biodistribution studies, U87MG-xenografted mice were injected with Ga-labeled compounds followed by small-animal PET imaging and Lu-labeled FAPI-02/04, respectively. Clinical PET/CT scans were performed 30 min post intravenous administration of Ga-FAPI-02/04. PET and MRI scans were co-registrated. Immunohistochemistry was done on 14 gliomas using a FAP-specific antibody.

Results: FAPI-02 and FAPI-04 showed high binding specificity to FAP. FAPI-04 demonstrated higher tumor accumulation and delayed elimination compared with FAPI-02 in preclinical studies. IDH-wildtype glioblastomas and grade III/IV, but not grade II, IDH-mutant gliomas showed elevated tracer uptake. In glioblastomas, we observed spots with increased uptake in projection on contrast-enhancing areas. Immunohistochemistry showed FAP-positive cells with mainly elongated cell bodies and perivascular FAP-positive cells in glioblastomas and an anaplastic IDH-mutant astrocytoma.

Conclusions: Using FAP-specific PET imaging, increased tracer uptake in IDH-wildtype glioblastomas and high-grade IDH-mutant astrocytomas, but not in diffuse astrocytomas, may allow non-invasive distinction between low-grade IDH-mutant and high-grade gliomas. Therefore, FAP-specific imaging in gliomas may be useful for follow-up studies although further clinical evaluation is required.
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http://dx.doi.org/10.1007/s00259-019-04444-yDOI Listing
November 2019

Lymph Node Involvement in Treatment-Naïve Prostate Cancer Patients: Correlation of PSMA PET/CT Imaging and Roach Formula in 280 Men in Radiotherapeutic Management.

J Nucl Med 2020 01 13;61(1):46-50. Epub 2019 Jul 13.

Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany

The importance of prostate-specific membrane antigen (PSMA) PET/CT for primary staging of treatment-naïve prostate cancer patients is still under debate. Therefore, the present study aimed to evaluate the role of PSMA PET/CT in detecting nodal metastases in a large cohort of men and compare imaging results with the risk of lymph node involvement based on the Roach formula. In total, 280 men with newly diagnosed prostate carcinoma were included in the present study. For all patients, PSMA PET/CT was performed for primary staging. Median age was 67 y (range, 38-84 y), and 84% of all patients were classified as high-risk according to the d'Amico criteria. The risk of lymph node involvement was calculated using the Roach formula and compared with the PSMA PET/CT results. PSMA-positive nodes were detected in 90 of 280 men (32.1%). Although most nodal metastases occurred within the pelvis, 36.0% were in extrapelvic sites. In 9 patients (3.2%), nodal metastases occurred in the Virchow node. After comparison of PSMA data with the results of the Roach formula, an area under the curve of 0.781 was obtained for the Roach predictions. For treatment-naïve prostate cancer patients, PSMA PET/CT is well suited for the detection of nodal metastases. However, the original Roach formula can still be used for a quick assessment of potential lymphatic spread in daily clinical routine.
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http://dx.doi.org/10.2967/jnumed.119.227637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954455PMC
January 2020