Publications by authors named "Wolfgang Weber"

331 Publications

Pre-therapeutic comparative dosimetry of Lu-rhPSMA-7.3 and Lu-PSMAI&T in patients with metastatic castration resistant prostate cancer (mCRPC).

J Nucl Med 2021 Sep 16. Epub 2021 Sep 16.

Nuclear Medicine, TU Munich.

Introduction: Radiohybrid prostate-specific membrane antigen (rhPSMA)-ligands allow for labelling with F and radiometals for endoradiotherapy. rhPSMA-7.3 is designated as lead compound with promising preclinical data for Lu-rhPSMA-7.3 indicating higher tumor uptake compared with Lu-PSMA-I&T. In this retrospective analysis we compared pre-therapeutic clinical dosimetry of both PSMA-ligands. Six mCRPC patients underwent both Lu-rhPSMA-7.3 and Lu-PSMA-I&T pre-therapeutic dosimetry. Whole-body scintigraphy was performed at 1h, 4h, 24h, 48h and 7d post injection. Regions of interest (ROI) covering the whole body, organs, bone marrow and tumor lesions per patient were drawn. Absorbed doses for individual patients and pre-therapeutic applications were calculated using OLINDA/EXM. To facilitate comparison of both ligands we introduced the therapeutic index (TI) defined as ratio of mean pre-therapeutic doses to tumor lesions over relevant organs-at-risk. Mean whole-body pre-therapeutic effective doses were 0.12±0.07 vs. 0.05±0.03 Sv/GBq and mean absorbed organ doses were e.g. 1.65±0.28 vs. 0.73±0.18 Gy/GBq for the kidneys; 0.19±0.09 vs. 0.07±0.03 Gy/GBq for the liver and 2.35±0.78 vs. 0.80±0.41 Gy/GBq for the parotid, for the bone marrow 0.67±0.62 vs. 0.30±0.27 Gy/GBq for Lu-rhPSMA-7.3 vs. Lu-PSMA-I&T, respectively. Tumor lesions received a mean absorbed doses of 6.44±6.44 vs. 2.64±2.24 Gy/GBq for Lu-rhPSMA-7.3 vs. Lu-PSMA-I&T, respectively. The mean TI(kidney) and TI(bone_marrow) were 3.7±2.2 vs. 3.6±2.2 and 15.2±10.2 vs. 15.1±10.2, for Lu-rhPSMA-7.3 vs. Lu-PSMA-I&T, respectively. Pre-therapeutic clinical dosimetry confirmed preclinical results with 2-3 times higher mean absorbed doses for tumors of Lu-rhPSMA-7.3 compared to Lu-PSMA-I&T. Absorbed doses to normal organs also tended to be higher for Lu-rhPSMA-7.3 resulting overall in a similar average TI for both radiopharmaceuticals with considerable inter-patient variability. Lu-rhPSMA-7.3 holds promise for similar therapeutic efficacy as Lu-PSMA-I&T at lower amounts of injected activity simplifying radiation safety measurements (especially for large patient numbers and/or dose escalation regimes).
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http://dx.doi.org/10.2967/jnumed.121.262671DOI Listing
September 2021

Molecular Imaging and the PD-L1 Pathway: From Bench to Clinic.

Front Oncol 2021 23;11:698425. Epub 2021 Aug 23.

Translational Medicine, Bristol Myers Squibb, Princeton, NJ, United States.

Programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors target the important molecular interplay between PD-1 and PD-L1, a key pathway contributing to immune evasion in the tumor microenvironment (TME). Long-term clinical benefit has been observed in patients receiving PD-(L)1 inhibitors, alone and in combination with other treatments, across multiple tumor types. PD-L1 expression has been associated with response to immune checkpoint inhibitors, and treatment strategies are often guided by immunohistochemistry-based diagnostic tests assessing expression of PD-L1. However, challenges related to the implementation, interpretation, and clinical utility of PD-L1 diagnostic tests have led to an increasing number of preclinical and clinical studies exploring interrogation of the TME by real-time imaging of PD-(L)1 expression by positron emission tomography (PET). PET imaging utilizes radiolabeled molecules to non-invasively assess PD-(L)1 expression spatially and temporally. Several PD-(L)1 PET tracers have been tested in preclinical and clinical studies, with clinical trials in progress to assess their use in a number of cancer types. This review will showcase the development of PD-(L)1 PET tracers from preclinical studies through to clinical use, and will explore the opportunities in drug development and possible future clinical implementation.
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http://dx.doi.org/10.3389/fonc.2021.698425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420047PMC
August 2021

Investigation of spleen CXCR4 expression by [Ga]Pentixafor PET in a cohort of 145 solid cancer patients.

EJNMMI Res 2021 Aug 21;11(1):77. Epub 2021 Aug 21.

Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203, Berlin, Germany.

Background: The chemokine receptor CXCR4 is frequently overexpressed and associated with adverse prognosis in most hematopoietic malignancies and solid cancers. Recently, CXCR4 molecular imaging using the CXCR4-specific positron emission tomography (PET) tracer Pentixafor ([Ga]Pentixafor) has become a well-established method to non-invasively measure CXCR4 expression in vivo. In previous Pentixafor imaging studies, highly variable CXCR4 tracer uptake to the spleen was observed.

Results: We investigated the hypothesis that enhanced spleen [Ga]Pentixafor uptake and thus CXCR4 expression in patients with solid tumors would indicate an activated spleen state and/or an association with clinical and prognostic features and survival parameters. In this retrospective study, [Ga]Pentixafor-PET images and patient records of 145 solid tumor patients representing 27 cancer entities were investigated for an association of spleen [Ga]Pentixafor uptake and clinical characteristics and outcome. Based on this assessment, we did not observe differences in clinical outcomes, measured by progression-free survival, overall survival and remission status neither within the entire cohort nor within subgroups of adrenal cancer, desmoplastic small round cell tumor, neuroendocrine tumors, non-small cell lung cancer, small cell lung cancer and pancreatic adenocarcinoma patients. No tumor entity showed especially high levels of spleen [Ga]Pentixafor uptake compared to others or a control cohort. However, when investigating laboratory parameters, there was a positive correlation of high spleen [Ga]Pentixafor uptake with leukocyte and/or platelet counts in neuroendocrine tumors, non-small cell lung cancer and small cell lung cancer.

Conclusion: Spleen [Ga]Pentixafor uptake was not associated with stage of disease and clinical outcomes in solid tumor patients. We identified positively associated platelet and/or leukocyte counts with spleen [Ga]Pentixafor uptake in neuroendocrine tumors, non-small cell lung cancer and small cell lung cancer, suggesting that splenic CXCR4 expression could possibly play a role in systemic immunity/inflammation in some types of solid tumors or a subgroup of patients within solid tumor entities.
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http://dx.doi.org/10.1186/s13550-021-00822-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380222PMC
August 2021

PSMA-ligand uptake can serve as a novel biomarker in primary prostate cancer to predict outcome after radical prostatectomy.

EJNMMI Res 2021 Aug 21;11(1):76. Epub 2021 Aug 21.

Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany.

Background: The prostate-specific membrane antigen (PSMA) is a relevant target in prostate cancer, and immunohistochemistry studies showed associations with outcome. PSMA-ligand positron emission tomography (PET) is increasingly used for primary prostate cancer staging, and the molecular imaging TNM classification (miTNM) standardizes its reporting. We aimed to investigate the potential of PET-imaging to serve as a noninvasive imaging biomarker to predict disease outcome in primary prostate cancer after radical prostatectomy (RP).

Methods: In this retrospective analysis, 186 primary prostate cancer patients treated with RP who had undergone a Ga-PSMA-11 PET up to three months prior to the surgery were included. Maximum standardized uptake value (SUV), SUV, tumor volume (TV) and total lesion (TL) were collected from PET-imaging. Moreover, clinicopathological information, including age, serum prostate-specific antigen (PSA) level, and pathological characteristics, was assessed for disease outcome prediction. A stage group system for PET-imaging findings based on the miTNM framework was developed.

Results: At a median follow-up after RP of 38 months (interquartile range (IQR) 22-53), biochemical recurrence (BCR) was observed in 58 patients during the follow-up period. A significant association between a positive surgical margin and miN status (miN1 vs. miN0, odds ratio (OR): 5.428, p = 0.004) was detected. miT status (miT ≥ 3a vs. miT < 3, OR: 2.696, p = 0.003) was identified as an independent predictor for Gleason score (GS) ≥ 8. Multivariate Cox regression analysis indicated that PSA level (hazard ratio (HR): 1.024, p = 0.014), advanced GS (GS ≥ 8 vs. GS < 8, HR: 3.253, p < 0.001) and miT status (miT ≥ 3a vs. miT < 3, HR: 1.941, p = 0.035) were independent predictors for BCR. For stage I disease as determined by PET-imaging, a shorter BCR-free survival was observed in the patients with higher SUV (IA vs. IB stage, log-rank, p = 0.022).

Conclusion: Preoperative miTNM classification from Ga-PSMA-11 PET correlates with postoperative GS, surgical margin status and time to BCR. The association between miTNM staging and outcome proposes Ga-PSMA-11 PET as a novel non-invasive imaging biomarker and potentially serves for ancillary pre-treatment stratification.
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http://dx.doi.org/10.1186/s13550-021-00818-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380207PMC
August 2021

The Influence of Specific Activity on the Biodistribution of F-rhPSMA-7.3: A Retrospective Analysis of Clinical Positron Emission Tomography Data.

J Nucl Med 2021 Aug 12. Epub 2021 Aug 12.

Nuclear Medicine, TU Munich.

We investigated whether the time between synthesis and injection and the resulting decrease in specific activity affects the normal organ and tumor uptake of the PSMA ligand, F-rhPSMA-7.3, in patients with prostate cancer. The biodistribution of F-rhPSMA-7.3 on PET/CT scans performed with a high specific activity (media = 178.9MBq/µg, = 42) and a low specific activity (media = 19.3MBq/µg, = 42) were compared. Tracer uptake by the parotid gland, submandibular gland and spleen was moderately, but significantly lower in the "low specific activity" group than in the "high specific activity" group (median SUVmean 16.7 vs. 19.2; 18.1 vs. 22.3, and 7.8 vs. 9.6, respectively). No other statistically significant differences were found for normal organs or tumor lesions. A 10-fold decrease in specific activity has only minor effects on the biodistribution of F-rhPSMA-7.3. These findings suggest that F-labeled PSMA ligands can be centrally produced and shipped to PET clinics in a similar way to F-fluorodeoxyglucose.
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http://dx.doi.org/10.2967/jnumed.121.262471DOI Listing
August 2021

Is Hypoxia a Factor Influencing PSMA-Directed Radioligand Therapy?-An In Silico Study on the Role of Chronic Hypoxia in Prostate Cancer.

Cancers (Basel) 2021 Jul 8;13(14). Epub 2021 Jul 8.

Department of Nuclear Medicine, Inselspital, University of Bern, 3010 Bern, Switzerland.

Radioligand therapy (RLT) targeting prostate specific-membrane antigen (PSMA) is an emerging treatment for metastatic castration-resistant prostate cancer (mCRPC). It administrates 225Ac- or 177Lu-labeled ligands for the targeted killing of tumor cells. Differently from X- or γ-ray, for the emitted α or β particles the ionization of the DNA molecule is less dependent on the tissue oxygenation status. Furthermore, the diffusion range of electrons in a tumor is much larger than the volume typically spanned by hypoxic regions. Therefore, hypoxia is less investigated as an influential factor for PSMA-directed RLT, in particular with β emitters. This study proposes an in silico approach to theoretically investigate the influence of tumor hypoxia on the PSMA-directed RLT. Based on mice histology images, the distribution of the radiopharmaceuticals was simulated with an in silico PBPK-based convection-reaction-diffusion model. Three anti-CD31 immunohistochemistry slices were used to simulate the tumor microenvironment. Ten regions of interest with varying hypoxia severity were analyzed. A kernel-based method was developed for dose calculation. The cell survival probability was calculated according to the linear-quadratic model. The statistical analysis performed on all the regions of interest (ROIs) shows more heterogeneous dose distributions obtained with 225Ac compared to 177Lu. The higher homogeneity of 177Lu-PSMA-ligand treatment is due to the larger range covered by the emitted β particles. The dose-to-tissue histogram (DTH) metric shows that in poorly vascularized ROIs only 10% of radiobiological hypoxic tissue receives the target dose using 177Lu-PSMA-ligand treatment. This percentage drops down to 5% using 225Ac. In highly vascularized ROIs, the percentage of hypoxic tissue receiving the target dose increases to more than 85% and 65% for the 177Lu and 225Ac-PSMA-ligands, respectively. The in silico study demonstrated that the reduced vascularization of the tumor strongly influences the dose delivered by PSMA-directed RLT, especially in hypoxic regions and consequently the treatment outcome.
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http://dx.doi.org/10.3390/cancers13143429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307065PMC
July 2021

Value of PET imaging for radiation therapy.

Nuklearmedizin 2021 Jul 14. Epub 2021 Jul 14.

Department of Nuclear Medicine, Technical University of Munich (TUM), Klinikum rechts der Isar, Munich, Germany.

This comprehensive review written by experts in their field gives an overview on the current status of incorporating positron emission tomography (PET) into radiation treatment planning. Moreover, it highlights ongoing studies for treatment individualisation and per-treatment tumour response monitoring for various primary tumours. Novel tracers and image analysis methods are discussed. The authors believe this contribution to be of crucial value for experts in the field as well as for policy makers deciding on the reimbursement of this powerful imaging modality.
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http://dx.doi.org/10.1055/a-1525-7029DOI Listing
July 2021

Value of PET imaging for radiation therapy.

Strahlenther Onkol 2021 Sep 14;197(9):1-23. Epub 2021 Jul 14.

Department of Nuclear Medicine, Technical University of Munich (TUM), Klinikum rechts der Isar, Munich, Germany.

This comprehensive review written by experts in their field gives an overview on the current status of incorporating positron emission tomography (PET) into radiation treatment planning. Moreover, it highlights ongoing studies for treatment individualisation and per-treatment tumour response monitoring for various primary tumours. Novel tracers and image analysis methods are discussed. The authors believe this contribution to be of crucial value for experts in the field as well as for policy makers deciding on the reimbursement of this powerful imaging modality.
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http://dx.doi.org/10.1007/s00066-021-01812-2DOI Listing
September 2021

The added value of PSMA PET/MR radiomics for prostate cancer staging.

Eur J Nucl Med Mol Imaging 2021 Jul 13. Epub 2021 Jul 13.

School of Medicine, Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.

Purpose: To evaluate the performance of combined PET and multiparametric MRI (mpMRI) radiomics for the group-wise prediction of postsurgical Gleason scores (psGSs) in primary prostate cancer (PCa) patients.

Methods: Patients with PCa, who underwent [ Ga]Ga-PSMA-11 PET/MRI followed by radical prostatectomy, were included in this retrospective analysis (n = 101). Patients were grouped by psGS in three categories: ISUP grades 1-3, ISUP grade 4, and ISUP grade 5. mpMRI images included T1-weighted, T2-weighted, and apparent diffusion coefficient (ADC) map. Whole-prostate segmentations were performed on each modality, and image biomarker standardization initiative (IBSI)-compliant radiomic features were extracted. Nine support vector machine (SVM) models were trained: four single-modality radiomic models (PET, T1w, T2w, ADC); three PET + MRI double-modality models (PET + T1w, PET + T2w, PET + ADC), and two baseline models (one with patient data, one image-based) for comparison. A sixfold stratified cross-validation was performed, and balanced accuracies (bAcc) of the predictions of the best-performing models were reported and compared through Student's t-tests. The predictions of the best-performing model were compared against biopsy GS (bGS).

Results: All radiomic models outperformed the baseline models. The best-performing (mean ± stdv [%]) single-modality model was the ADC model (76 ± 6%), although not significantly better (p > 0.05) than other single-modality models (T1w: 72 ± 3%, T2w: 73 ± 2%; PET: 75 ± 5%). The overall best-performing model combined PET + ADC radiomics (82 ± 5%). It significantly outperformed most other double-modality (PET + T1w: 74 ± 5%, p = 0.026; PET + T2w: 71 ± 4%, p = 0.003) and single-modality models (PET: p = 0.042; T1w: p = 0.002; T2w: p = 0.003), except the ADC-only model (p = 0.138). In this initial cohort, the PET + ADC model outperformed bGS overall (82.5% vs 72.4%) in the prediction of psGS.

Conclusion: All single- and double-modality models outperformed the baseline models, showing their potential in the prediction of GS, even with an unbalanced cohort. The best-performing model included PET + ADC radiomics, suggesting a complementary value of PSMA-PET and ADC radiomics.
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http://dx.doi.org/10.1007/s00259-021-05430-zDOI Listing
July 2021

Whole-body uptake classification and prostate cancer staging in Ga-PSMA-11 PET/CT using dual-tracer learning.

Eur J Nucl Med Mol Imaging 2021 Jul 7. Epub 2021 Jul 7.

School of Medicine, Department of Nuclear Medicine, Technische Universität München, Munich, Germany.

Purpose: In PSMA-ligand PET/CT imaging, standardized evaluation frameworks and image-derived parameters are increasingly used to support prostate cancer staging. Clinical applicability remains challenging wherever manual measurements of numerous suspected lesions are required. Deep learning methods are promising for automated image analysis, typically requiring extensive expert-annotated image datasets to reach sufficient accuracy. We developed a deep learning method to support image-based staging, investigating the use of training information from two radiotracers.

Methods: In 173 subjects imaged with Ga-PSMA-11 PET/CT, divided into development (121) and test (52) sets, we trained and evaluated a convolutional neural network to both classify sites of elevated tracer uptake as nonsuspicious or suspicious for cancer and assign them an anatomical location. We evaluated training strategies to leverage information from a larger dataset of F-FDG PET/CT images and expert annotations, including transfer learning and combined training encoding the tracer type as input to the network. We assessed the agreement between the N and M stage assigned based on the network annotations and expert annotations, according to the PROMISE miTNM framework.

Results: In the development set, including F-FDG training data improved classification performance in four-fold cross validation. In the test set, compared to expert assessment, training with F-FDG data and the development set yielded 80.4% average precision [confidence interval (CI): 71.1-87.8] for identification of suspicious uptake sites, 77% (CI: 70.0-83.4) accuracy for anatomical location classification of suspicious findings, 81% agreement for identification of regional lymph node involvement, and 77% agreement for identification of metastatic stage.

Conclusion: The evaluated algorithm showed good agreement with expert assessment for identification and anatomical location classification of suspicious uptake sites in whole-body Ga-PSMA-11 PET/CT. With restricted PSMA-ligand data available, the use of training examples from a different radiotracer improved performance. The investigated methods are promising for enabling efficient assessment of cancer stage and tumor burden.
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http://dx.doi.org/10.1007/s00259-021-05473-2DOI Listing
July 2021

A phase I study of a PARP1-targeted topical fluorophore for the detection of oral cancer.

Eur J Nucl Med Mol Imaging 2021 Oct 5;48(11):3618-3630. Epub 2021 May 5.

Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

Background: Visual inspection and biopsy is the current standard of care for oral cancer diagnosis, but is subject to misinterpretation and consequently to misdiagnosis. Topically applied PARPi-FL is a molecularly specific, fluorescent contrast-based approach that may fulfill the unmet need for a simple, in vivo, non-invasive, cost-effective, point-of-care method for the early diagnosis of oral cancer. Here, we present results from a phase I safety and feasibility study on fluorescent, topically applied PARPi-FL. Twelve patients with a histologically proven oral squamous cell carcinoma (OSCC) gargled a PARPi-FL solution for 60 s (15 mL, 100 nM, 250 nM, 500 nM, or 1000 nM), followed by gargling a clearing solution for 60 s. Fluorescence measurements of the lesion and surrounding oral mucosa were taken before PARPi-FL application, after PARPi-FL application, and after clearing. Blood pressure, oxygen levels, clinical chemistry, and CBC were obtained before and after tracer administration.

Results: PARPi-FL was well-tolerated by all patients without any safety concerns. When analyzing the fluorescence signal, all malignant lesions showed a significant differential in contrast after administration of PARPi-FL, with the highest increase occurring at the highest dose level (1000 nM), where all patients had a tumor-to-margin fluorescence signal ratio of >3. A clearing step was essential to increase signal specificity, as it clears unbound PARPi-FL trapped in normal anatomical structures. PARPi-FL tumor cell specificity was confirmed by ex vivo tabletop confocal microscopy. We have demonstrated that the fluorescence signal arose from the nuclei of tumor cells, endorsing our macroscopic findings.

Conclusions: A PARPi-FL swish & spit solution is a rapid and non-invasive diagnostic tool that preferentially localizes fluorescent contrast to OSCC. This technique holds promise for the early detection of OSCC based on in vivo optical evaluation and targeted biopsy of suspicious lesions in the oral cavity.

Trial Registration: Clinicaltrials.gov -NCT03085147, registered on March 21st, 2017.
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http://dx.doi.org/10.1007/s00259-021-05372-6DOI Listing
October 2021

Imaging of cardiac fibroblast activation in a patient after acute myocardial infarction using Ga-FAPI-04.

J Nucl Cardiol 2021 Apr 15. Epub 2021 Apr 15.

Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675, Munich, Germany.

Our previous study has demonstrated the feasibility of noninvasive imaging of fibroblast activation protein (FAP)-expression after myocardial infarction (MI) in MI-territory in a rat model with Ga-FAPI-04-PET. In the current extended clinical case, we sought to delineate cardiac uptake of Ga-FAPI-04 in a patient after MI with clinical indication for the evidence of fibroblast activation. Carcinoma patients without cardiac disease underwent Ga-FAPI-04-PET/CT as control. The patient with one-vessel disease underwent dynamic Ga-FAPI-04-cardiac-PET/CMR for 60 minutes. Correlation of cardiac Ga-FAPI-04 uptake with clinical findings, ECG, echocardiography, coronary-arteriography and enhanced cardiac-MRI with T1 MOLLI and ECV mapping were performed. No uptake was found in normal myocardium and in mature scar. A focal intense Ga-FAPI-04 uptake with continuous wash-out in the infarct territory of coronary occlusion correlating with T1 and ECV mapping was observed. The uptake of Ga-FAPI-04 extends beyond the actual infarcted area and overestimates the infarct size as confirmed by follow-up CMR.
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http://dx.doi.org/10.1007/s12350-021-02603-zDOI Listing
April 2021

Effective rational humanization of a PASylated anti-galectin-3 Fab for the sensitive PET imaging of thyroid cancer in vivo.

Sci Rep 2021 Apr 1;11(1):7358. Epub 2021 Apr 1.

Lehrstuhl für Biologische Chemie, Technische Universität München, 85354, Freising (Weihenstephan), Germany.

The lack of a non-invasive test for malignant thyroid nodules makes the diagnosis of thyroid cancer (TC) challenging. Human galectin-3 (hGal3) has emerged as a promising target for medical TC imaging and diagnosis because of its exclusive overexpression in malignant thyroid tissues. We previously developed a human-chimeric αhGal3 Fab fragment derived from the rat monoclonal antibody (mAb) M3/38 with optimized clearance characteristics using PASylation technology. Here, we describe the elucidation of the hGal3 epitope recognized by mAb M3/38, X-ray crystallographic analysis of its complex with the chimeric Fab and, based on the three-dimensional structure, the rational humanization of the Fab by CDR grafting. Four CDR-grafted versions were designed using structurally most closely related fully human immunoglobulin V/V regions of which one-employing the acceptor framework regions of the HIV-1 neutralizing human antibody m66-showed the highest antigen affinity. By introducing two additional back-mutations to the rodent donor sequence, an affinity toward hGal3 indistinguishable from the chimeric Fab was achieved (K = 0.34 ± 0.02 nM in SPR). The PASylated humanized Fab was site-specifically labelled with the fluorescent dye Cy7 and applied for the immuno-histochemical staining of human tissue sections representative for different TCs. The same protein was conjugated with the metal chelator Dfo, followed by radiolabelling with Zr(IV). The resulting protein tracer allowed the highly sensitive and specific PET/CT imaging of orthotopic tumors in mice, which was confirmed by quantitative analysis of radiotracer accumulation. Thus, the PASylated humanized αhGal3 Fab offers clinical potential for the diagnostic imaging of TC.
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http://dx.doi.org/10.1038/s41598-021-86641-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016950PMC
April 2021

Detection efficacy of F-rhPSMA-7.3 PET/CT and impact on patient management in patients with biochemical recurrence of prostate cancer after radical prostatectomy and prior to potential salvage treatment.

J Nucl Med 2021 Mar 12. Epub 2021 Mar 12.

Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Germany, Germany.

Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands are a new class of F-labeled PSMA-targeting agents. F-rhPSMA-7.3 is a lead compound which is currently under investigation in two multicenter phase III trials for PET-imaging. Here, we report the first retrospective data on its detection efficacy and potential impact on clinical management in a homogeneous cohort of patients with biochemical recurrence after radical prostatectomy, and prior to any salvage therapy. 242 patients (median [range] PSA, 0.60 [0.2-60.8] ng/mL) who underwent F-rhPSMA-7.3 PET/CT were retrospectively selected from the institutions' database. Images were re-read by an experienced nuclear medicine physician. Lesion detection rates were stratified by PSA. Further, potential management before and after PET was assessed by an interdisciplinary simulated tumor board and categorized (major vs. minor vs. no therapeutic change). The distribution of management change identified in each PSA subgroup was determined. In total, 176/242 (72.7%) patients showed PSMA-ligand positive findings. F-rhPSMA-7.3 detection rates were 61.8% (63/102), 67.9% (38/56), 81.1% (30/37) and 95.7% (45/47) for PSA-levels of 0.2-<0.5 ng/mL, 0.5-<1 ng/mL, 1-<2 ng/mL and ≥2 ng/mL, respectively. F-rhPSMA-7.3 PET/CT revealed local recurrence, pelvic lymph node metastases, retroperitoneal lymph nodes metastases, supradiaphragmatic lymph nodes, bone metastases, and visceral metastases in 48.8% ( = 118), 28.9% ( = 70), 6.6% ( = 16), 1.2% ( = 3), 13.2% ( = 32) and 1.2% ( = 3) of patients, respectively. Notably, bone lesions were identified in 8.8% of patients (9/102) with PSA <0.5 ng/mL. Results from the interdisciplinary simulated tumor board indicated change of therapeutic management in 153/242 patients (63.2%) with 54/242 (22.3%) considered major and 99/242 (40.9%) minor, respectively. F-rhPSMA-7.3 PET/CT did not prompt any therapeutic changes in 64/242 patients (26.4%). F-rhPSMA-7.3 PET offers high detection efficacy in patients with biochemical recurrence after radical prostatectomy, and prior to potential salvage therapy, and results in a potential change in treatment plans in nearly 2/3 of patients. Keywords: Biochemical recurrence; hybrid imaging; positron emission tomography; prostate cancer; prostate-specific membrane antigen.
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http://dx.doi.org/10.2967/jnumed.120.260091DOI Listing
March 2021

The IMiD target CRBN determines HSP90 activity toward transmembrane proteins essential in multiple myeloma.

Mol Cell 2021 03 10;81(6):1170-1186.e10. Epub 2021 Feb 10.

Department of Medicine III, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany; TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, 81675 Munich, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address:

The complex architecture of transmembrane proteins requires quality control (QC) of folding, membrane positioning, and trafficking as prerequisites for cellular homeostasis and intercellular communication. However, it has remained unclear whether transmembrane protein-specific QC hubs exist. Here we identify cereblon (CRBN), the target of immunomodulatory drugs (IMiDs), as a co-chaperone that specifically determines chaperone activity of HSP90 toward transmembrane proteins by means of counteracting AHA1. This function is abrogated by IMiDs, which disrupt the interaction of CRBN with HSP90. Among the multiple transmembrane protein clients of CRBN-AHA1-HSP90 revealed by cell surface proteomics, we identify the amino acid transporter LAT1/CD98hc as a determinant of IMiD activity in multiple myeloma (MM) and present an Anticalin-based CD98hc radiopharmaceutical for MM radio-theranostics. These data establish the CRBN-AHA1-HSP90 axis in the biogenesis of transmembrane proteins, link IMiD activity to tumor metabolism, and nominate CD98hc and LAT1 as attractive diagnostic and therapeutic targets in MM.
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http://dx.doi.org/10.1016/j.molcel.2020.12.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980223PMC
March 2021

Reply: Radioguided Surgery.

J Nucl Med 2021 04 5;62(4):592. Epub 2021 Feb 5.

Technical University of Munich Ismaningerstrasse 22 München 81675, Germany E-mail:

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http://dx.doi.org/10.2967/jnumed.121.261917DOI Listing
April 2021

Performance of [Ga]Ga-PSMA-11 PET/CT in patients with recurrent prostate cancer after prostatectomy-a multi-centre evaluation of 2533 patients.

Eur J Nucl Med Mol Imaging 2021 08 4;48(9):2925-2934. Epub 2021 Feb 4.

Department of Nuclear Medicine, Technical University of Munich, Munich, Germany.

Purpose: To evaluate the performance of [Ga]Ga-PSMA-11 PET/CT in the diagnosis of recurrent prostate cancer (PC) after prostatectomy in a large multicentre cohort.

Methods: The centres, which contributed to this study, were the departments of nuclear medicine of Heidelberg (Germany), Technical University of Munich (Germany) and Albert Einstein Hospital of São Paulo (Brazil). A total of 2533 patients who were scanned with [Ga]Ga-PSMA-11 PET/CT at 1 h p.i. due to recurrent PC after prostatectomy were included in this retrospective analysis. Exclusion criteria were as follows: patients with untreated primary tumour, previous chemotherapy or Xofigo®; those previously treated with exclusively external beam radiation therapy or HIFU; those referred for PSMA-therapy; and those treated with ADT (including first- and second-generation ADT) within the last 6 months. Potential influences of different factors such as PSA level, PSA doubling-time (PSA), PSA velocity (PSA), Gleason Score (GSC, including the separate analysis of 7a and 7b), age and amount of injected tracer were evaluated in a multivariable analysis.

Results: The rate of pathologic PET/CT-scans was 43% for PSA ≤ 0.2 ng/ml, 58% for PSA > 0.2 to ≤ 0.5, 72% for PSA > 0.5 to ≤ 1.0 and increased to a maximum of 93% for PSA > 10 ng/ml. A pathological PET/CT was significantly (p = 0.001) associated with PSA level and higher GSC. Amount of injected tracer, age, PSA and PSA were not associated with a higher probability of a pathological scan.

Conclusion: [Ga]Ga-PSMA-11 PET/CT at 1 h p.i. confirmed its high performance in the largest patient cohort yet analysed. Tumour detection showed a clear association with higher PSA and higher GSC. No association was found between a pathological [Ga]Ga-PSMA-11 PET/CT and age, amount of injected tracer, PSA or PSA.
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http://dx.doi.org/10.1007/s00259-021-05189-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263399PMC
August 2021

Synthesis and Preclinical Evaluation of a Ga-Labeled Adnectin, Ga-BMS-986192, as a PET Agent for Imaging PD-L1 Expression.

J Nucl Med 2021 Sep 30;62(9):1228-1234. Epub 2021 Jan 30.

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

Blocking the interaction of the immune checkpoint molecule programmed cell death protein-1 and its ligand, PD-L1, using specific antibodies has been a major breakthrough for immune oncology. Whole-body PD-L1 expression PET imaging may potentially allow for a better prediction of response to programmed cell death protein-1-targeted therapies. Imaging of PD-L1 expression is feasible by PET with the adnectin protein F-BMS-986192. However, radiofluorination of proteins such as BMS-986192 remains complex and labeling yields are low. The goal of this study was therefore the development and preclinical evaluation of a Ga-labeled adnectin protein (Ga-BMS-986192) to facilitate clinical trials. Ga labeling of DOTA-conjugated adnectin (BXA-206362) was performed in NaOAc-buffer at pH 5.5 (50°C, 15 min). In vitro stability in human serum at 37°C was analyzed using radio-thin layer chromatography and radio-high-performance liquid chromatography. PD-L1 binding assays were performed using the transduced PD-L1-expressing lymphoma cell line U-698-M and wild-type U-698-M cells as a negative control. Immunohistochemical staining studies, biodistribution studies, and small-animal PET studies of Ga-BMS-986192 were performed using PD-L1-positive and PD-L1-negative U-698-M-bearing NSG mice. Ga-BMS-986192 was obtained with quantitative radiochemical yields of more than 97% and with high radiochemical purity. In vitro stability in human serum was at least 95% after 4 h of incubation. High and specific binding of Ga-BMS-986192 to human PD-L1-expressing cancer cells was confirmed, which closely correlates with the respective PD-L1 expression level determined by flow cytometry and immunohistochemistry staining. In vivo, Ga-BMS-986192 uptake was high at 1 h after injection in PD-L1-positive tumors (9.0 ± 2.1 percentage injected dose [%ID]/g) and kidneys (56.9 ± 9.2 %ID/g), with negligible uptake in other tissues. PD-L1-negative tumors demonstrated only background uptake of radioactivity (0.6 ± 0.1 %ID/g). Coinjection of an excess of unlabeled adnectin reduced tumor uptake of PD-L1 by more than 80%. Ga-BMS-986192 enables easy radiosynthesis and shows excellent in vitro and in vivo PD-L1-targeting characteristics. The high tumor uptake combined with low background accumulation at early imaging time points demonstrates the feasibility of Ga-BMS-986192 for imaging of PD-L1 expression in tumors and is encouraging for further clinical applications of PD-L1 ligands.
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http://dx.doi.org/10.2967/jnumed.120.258384DOI Listing
September 2021

Automated synthesis of [F]Ga-rhPSMA-7/ -7.3: results, quality control and experience from more than 200 routine productions.

EJNMMI Radiopharm Chem 2021 Jan 23;6(1). Epub 2021 Jan 23.

Chair of Pharmaceutical Radiochemistry, Technical University of Munich, Walther-Meißner-Str. 3, 85748, Garching, Germany.

Introduction: The radiohybrid (rh) prostate-specific membrane antigen (PSMA)-targeted ligand [F]Ga-rhPSMA-7 has previously been clinically assessed and demonstrated promising results for PET-imaging of prostate cancer. The ligand is present as a mixture of four stereoisomers ([F]Ga-rhPSMA-7.1, - 7.2, - 7.3 and - 7.4) and after a preclinical isomer selection process, [F]Ga-rhPSMA-7.3 has entered formal clinical trials. Here we report on the establishment of a fully automated production process for large-scale production of [F]Ga-rhPSMA-7/ -7.3 under GMP conditions (EudraLex).

Methods: [F]Fluoride in highly enriched [O]HO was retained on a strong anion exchange cartridge, rinsed with anhydrous acetonitrile and subsequently eluted with a solution of [K ⊂ 2.2.2]OH in anhydrous acetonitrile into a reactor containing Ga-rhPSMA ligand and oxalic acid in DMSO. F-for-F isotopic exchange at the Silicon-Fluoride Acceptor (SiFA) was performed at room temperature, followed by dilution with buffer and cartridge-based purification. Optimum process parameters were determined on the laboratory scale and thereafter implemented into an automated synthesis. Data for radiochemical yield (RCY), purity and quality control were analyzed for 243 clinical productions (160 for [F]Ga-rhPSMA-7; 83 for [F]Ga-rhPSMA-7.3).

Results: The automated production of [F]Ga-rhPSMA-7 and the single isomer [F]Ga-rhPSMA-7.3 is completed in approx. 16 min with an average RCY of 49.2 ± 8.6% and an excellent reliability of 98.8%. Based on the different starting activities (range: 31-130 GBq, 89 ± 14 GBq) an average molar activity of 291 ± 62 GBq/μmol (range: 50-450 GBq/μmol) was reached for labeling of 150 nmol (231 μg) precursor. Radiochemical purity, as measured by radio-high performance liquid chromatography and radio-thin layer chromatography, was 99.9 ± 0.2% and 97.8 ± 1.0%, respectively.

Conclusion: This investigation demonstrates that F-for-F isotopic exchange is well suited for the fast, efficient and reliable automated routine production of F-labeled PSMA-targeted ligands. Due to its simplicity, speed and robustness the development of further SiFA-based radiopharmaceuticals is highly promising and can be of far-reaching importance for future theranostic concepts.
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http://dx.doi.org/10.1186/s41181-021-00120-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826325PMC
January 2021

Comparative Preclinical Biodistribution, Dosimetry, and Endoradiotherapy in Metastatic Castration-Resistant Prostate Cancer Using F/Lu-rhPSMA-7.3 and Lu-PSMA I&T.

J Nucl Med 2021 Aug 18;62(8):1106-1111. Epub 2020 Dec 18.

Department of Nuclear Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; and

Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands are applicable as radiochemical twins for both diagnostic PET imaging and endoradiotherapy. On the basis of preliminary data as a diagnostic ligand, the isomer rhPSMA-7.3 is a promising candidate for potential endoradiotherapy. The aim of this preclinical evaluation was to assess the biodistribution, dosimetry, and therapeutic efficacy of F/Lu-rhPSMA-7.3 in comparison to the established therapeutic agent Lu-PSMA I&T (imaging and therapy). The biodistribution of F/Lu-rhPSMA-7.3 and Lu-PSMA I&T was determined in LNCaP tumor-bearing severe combined immunodeficiency (SCID) mice after sacrifice at defined time points up to 7 d ( = 5). Organs and tumors were dissected, percentage injected dose per gram (%ID/g) was determined, and dosimetry was calculated using OLINDA/EXM, version 1.0. The therapeutic efficacy of a single 30-MBq dose of F/Lu-rhPSMA-7.3 ( = 7) was compared with that of Lu-PSMA I&T in treatment groups ( = 7) and control groups ( = 6-7) using C4-2 tumor-bearing SCID mice by evaluating tumor growth and survival over 6 wk after treatment. The biodistribution of F/Lu-rhPSMA-7.3 revealed fast blood clearance (0.63 %ID/g at 1 h after injection), and the highest activity uptake was in the spleen and kidneys, particularly in the first hour (33.25 %ID/g and 207.6 %ID/g, respectively, at 1 h after injection), indicating a renal excretion pathway. Compared with Lu-PSMA I&T, F/Lu-rhPSMA-7.3 exhibited an initial (1 h) 2.6-fold higher tumor uptake in LNCaP xenografts and a longer retention (4.5 %ID/g vs. 0.9 %ID/g at 168 h). The tumor dose of F/Lu-rhPSMA-7.3 was substantially higher (e.g., 7.47 vs. 1.96 µGy/MBq at 200 mm) than that of Lu-PSMA I&T. In most organs, absorbed doses were higher for Lu-PSMA I&T. A significantly greater tumor size reduction was shown for a single dose of F/Lu-rhPSMA-7.3 than for Lu-PSMA I&T at the end of the experiment ( = 0.0167). At the predefined termination of the experiment at 6 wk, 7 of 7 and 3 of 7 mice were still alive in the F/Lu-rhPSMA-7.3 and Lu-PSMA I&T groups, respectively, compared with the respective control groups, with 0 of 7 and 0 of 6 mice. Compared with Lu-PSMA I&T, F/Lu-rhPSMA-7.3 can be considered a suitable candidate for clinical translation because it has similar clearance kinetics and a similar radiation dose to healthy organs but superior tumor uptake and retention. Preliminary treatment experiments showed a favorable antitumor response.
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http://dx.doi.org/10.2967/jnumed.120.254516DOI Listing
August 2021

Imaging atherosclerotic plaques by targeting Galectin-3 and activated macrophages using (Zr)-DFO- Galectin3-F(ab') mAb.

Theranostics 2021 1;11(4):1864-1876. Epub 2021 Jan 1.

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

The high expression of Galectin-3 (Gal3) in macrophages of atherosclerotic plaques suggests its participation in atherosclerosis pathogenesis, and raises the possibility to use it as a target to image disease severity . Here, we explored the feasibility of tracking atherosclerosis by targeting Gal3 expression in plaques of apolipoprotein E knockout (ApoE-KO) mice PET imaging. Targeting of Gal3 in M0-, M1- and M2 (M2a/M2c)-polarized macrophages was assessed using a Gal3-F(ab') mAb labeled with AlexaFluor®488 and Zr- desferrioxamine-thioureyl-phenyl-isothiocyanate (DFO). To visualize plaques , ApoE-KO mice were injected i.v. with Zr-DFO-Gal3-F(ab') mAb and imaged via PET/CT 48 h post injection. Whole length aortas harvested from euthanized mice were processed for Sudan-IV staining, autoradiography, and immunostaining for Gal3, CD68 and α-SMA expression. To confirm accumulation of the tracer in plaques, ApoE-KO mice were injected i.v. with Cy5.5-Gal3-F(ab') mAb, euthanized 48 h post injection, followed by cryosections of the body and acquisition of fluorescent images. To explore the clinical potential of this imaging modality, immunostaining for Gal3, CD68 and α-SMA expression were carried out in human plaques. Single cell RNA sequencing (scRNA-Seq) analyses were performed to measure LGALS3 (i.e. a synonym for Gal3) gene expression in each macrophage of several subtypes present in murine or human plaques. Preferential binding to M2 macrophages was observed with both AlexaFluor®488-Gal3-F(ab') and Zr-DFO-Gal3-F(ab') mAbs. Focal and specific Zr-DFO-Gal3-F(ab') mAb uptake was detected in plaques of ApoE-KO mice by PET/CT. Autoradiography and immunohistochemical analyses of aortas confirmed the expression of Gal3 within plaques mainly in macrophages. Moreover, a specific fluorescent signal was visualized within the lesions of vascular structures burdened by plaques in mice. Gal3 expression in human plaques showed similar Gal3 expression patterns when compared to their murine counterparts. Our data reveal that Zr-DFO-Gal3-F(ab') mAb PET/CT is a potentially novel tool to image atherosclerotic plaques at different stages of development, allowing knowledge-based tailored individual intervention in clinically significant disease.
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http://dx.doi.org/10.7150/thno.50247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778602PMC
August 2021

Mars Shot for Nuclear Medicine, Molecular Imaging, and Molecularly Targeted Radiopharmaceutical Therapy.

J Nucl Med 2021 01;62(1):6-14

Departments of Radiology and Physics, University of Iowa, Iowa City, Iowa.

The Society of Nuclear Medicine and Molecular Imaging created the Value Initiative in 2017 as a major component of its strategic plan to further demonstrate the value of molecular imaging and molecularly targeted radiopharmaceutical therapy to patients, physicians, payers, and funding agencies. The research and discovery domain, 1 of 5 under the Value Initiative, has a goal of advancing the research and development of diagnostic and therapeutic nuclear medicine. Research and discovery efforts and achievements are essential to ensure a bright future for NM and to translate science to practice. Given the remarkable progress in the field, leaders from the research and discovery domain and society councils identified 5 broad areas of opportunity with potential for substantive growth and clinical impact. This article discusses these 5 growth areas, identifying specific areas of particularly high importance for future study and development. As there was an understanding that goals should be both visionary yet achievable, this effort was called the Mars shot for nuclear medicine.
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http://dx.doi.org/10.2967/jnumed.120.253450DOI Listing
January 2021

Activity and Adverse Events of Actinium-225-PSMA-617 in Advanced Metastatic Castration-resistant Prostate Cancer After Failure of Lutetium-177-PSMA.

Eur Urol 2021 03 5;79(3):343-350. Epub 2020 Dec 5.

Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany; German Cancer Consortium (DKTK), partnersite Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Beta-emitting Lu-177-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a new option for metastatic castration-resistant prostate cancer (mCRPC), but its antitumor effect can decrease over time.

Objective: To report the safety and activity of alpha-emitting Ac-225-PSMA-617 RLT in mCRPC that has progressed after Lu-177-PSMA.

Design, Setting, And Participants: Twenty-six patients were treated under a compassionate use protocol. The eligibility criteria included previous treatment with abiraterone or enzalutamide, previous taxane-based chemotherapy, progression after Lu-177-PSMA, and positive PSMA-ligand uptake. The median number of previous mCRPC regimens was 6. Ac-225-PSMA-617 was given every 8 wk until progression/intolerable side effects.

Outcome Measurements And Statistical Analysis: Prostate-specific antigen (PSA) decline, PSA progression-free survival (PSA-PFS), clinical progression-free survival (cPFS), overall survival (OS), and toxicity were measured.

Results And Limitations: Sixty-one cycles of Ac-225-PSMA-617 (median number of cycles 2; median activity 9 MBq) were administered. A PSA decline of ≥50% was achieved in 17/26 patients. The median PSA-PFS, cPFS, and OS periods were 3.5 (95% confidence interval [CI] 1.8-11.2), 4.1 (95% CI 3-14.8), and 7.7 (95% CI 4.5-12.1) mo, respectively. Liver metastases were associated with shorter PSA-PFS (median 1.9 vs 4.0 mo; p = 0.02), cPFS (median 1.8 vs 5.2 mo; p = 0.001), and OS (median 4.3 vs 10.4 mo; p = 0.01). Hematological grade 3/4 toxicities were anemia (35%), leucopenia (27%), and thrombocytopenia (19%). All patients experienced grade 1/2 xerostomia. Two and six patients stopped due to hematological toxicity and xerostomia, respectively. A limitation is the retrospective design.

Conclusions: Ac-225-PSMA-617 showed measurable antitumor effect after Lu-177-PSMA failure in late-stage mCRPC. Grade 3/4 hematological side effects were observed in up to one-third of patients, and xerostomia led to treatment halt in a relevant number of patients.

Patient Summary: Ac-225-labeled prostate-specific membrane antigen (PSMA)-617 therapy showed substantial antitumor effect in late metastatic castration-resistant prostate cancer after Lu-177-PSMA failure. However, dry mouth is a common side effect that caused about a quarter of patients to stop therapy.
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http://dx.doi.org/10.1016/j.eururo.2020.11.013DOI Listing
March 2021

Matched-Pair Comparison of Ga-PSMA-11 and F-rhPSMA-7 PET/CT in Patients with Primary and Biochemical Recurrence of Prostate Cancer: Frequency of Non-Tumor-Related Uptake and Tumor Positivity.

J Nucl Med 2021 Aug 4;62(8):1082-1088. Epub 2020 Dec 4.

Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany;

Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands are a new class of prostate cancer theranostic agents. F-rhPSMA-7 offers the advantages of F labeling and low urinary excretion compared with Ga-PSMA-11. Here, we compare the frequency of non-tumor-related uptake and tumor positivity with Ga-PSMA-11 and F-rhPSMA-7 in patients with primary or recurrent prostate cancer. This retrospective matched-pair comparison matched 160 F-rhPSMA-7 with 160 Ga-PSMA-11 PET/CT studies for primary staging ( = 33) and biochemical recurrence ( = 127) according to clinical characteristics. Two nuclear medicine physicians reviewed all scans, first identifying all PET-positive lesions and then differentiating lesions suggestive of prostate cancer from those that were benign, on the basis of known pitfalls and ancillary information from CT. For each region, the SUV of the lesion with the highest PSMA ligand uptake was noted. Tumor positivity rates were determined, and SUV was compared separately for each tracer. F-rhPSMA-7 and Ga-PSMA-11 PET revealed 566 and 289 PSMA ligand-positive lesions, respectively. Of these, 379 and 100 lesions, equaling 67.0% and 34.6%, respectively, of all PSMA-positive lesions, were considered benign. The distribution of their etiology was similar (42%, 24%, and 25% with F-rhPSMA-7 vs. 32%, 24%, and 38% with Ga-PSMA-11 for ganglia, bone, and unspecific lymph nodes, respectively). All primary tumors were positive with both agents ( = 33 each), whereas slightly more metastatic lesions were observed with Ga-PSMA-11 in both disease stages (113 for F-rhPSMA-7 and 124 for Ga-PSMA-11). The SUV of F-rhPSMA-7 and Ga-PSMA-11 did not differ ( > 0.05) in local recurrence or primary prostate cancer; however, the tumor-to-bladder ratio was significantly higher with F-rhPSMA-7 (4.9 ± 5.3 vs. 2.2 ± 3.7, = 0.02, for local recurrence; 9.8 ± 9.7 vs. 2.3 ± 2.6, < 0.001, for primary prostate cancer). The tumor positivity rate was consistently high for Ga-PSMA-11 and F-rhPSMA-7. Both tracers revealed a considerable number of areas of uptake that were reliably identified as benign by trained physicians making use of corresponding morphologic imaging and known PSMA pitfalls. These were more frequent with F-rhPSMA-7. However, the matched-pair comparison could have introduced a source of bias. Adequate reader training can allow physicians to differentiate benign uptake from disease and be able to benefit from the logistical and clinical advantages of F-rhPSMA-7.
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http://dx.doi.org/10.2967/jnumed.120.251447DOI Listing
August 2021

Positive Predictive Value and Correct Detection Rate of F-rhPSMA-7 PET in Biochemically Recurrent Prostate Cancer Validated by Composite Reference Standard.

J Nucl Med 2021 Jul 13;62(7):968-974. Epub 2020 Nov 13.

School of Medicine, Department of Nuclear Medicine, Technical University Munich, Munich, Germany.

The objective of this retrospective study was to assess the detection rate (DR), positive predictive value (PPV), and correct detection rate (CDR) of F-rhPSMA-7 PET/CT in biochemical recurrence (BCR) of prostate cancer (PCa) after radical prostatectomy (RP) using composite validation. F-rhPSMA-7 PET/CT scans of patients with BCR between July 2017 and June 2018 were retrospectively reviewed. All suspicious lesions were recorded. The reference standard was histopathology or combinations of histopathology, imaging, or prostate-specific antigen (PSA) follow up, defined as composite reference standard. DR was calculated as the proportion of PSMA PET-positive patients to all patients independent of the reference standard, whereas the CDR was the percentage of patients who had at least 1 true-positive PSMA PET lesion localized that corresponded with the reference standard. The PPV was defined as the proportion of patients who had true-positive to all positive findings. The correlation between DR and patient characteristics was evaluated. A total of 532 patients with a median PSA level of 0.97 ng/mL (interquartile range: 0.41-2.46 ng/mL) were included. Of these, 162 patients had composite follow-up at a median duration of 5.6 mo (range: 1.1-14.2 mo). The proportion of patients who had no lesion visualized on PET/CT, localized disease, and any distant metastases (M1) were 20%, 43%, and 37%, respectively. PET DR among all patients was 80%. On a per-patient basis, the PPV of F-rhPSMA-7 PET/CT in the composite cohort was 88%, and the CDR was 70%. The PPV in the histopathology-proven cohort was 91%, and the CDR in this subgroup was 73%. In patients with PSA levels ≥ 1 ng/mL the DR and PPV were 90% and 91%, respectively, resulting in a CDR of 82%. In patients with PSA levels < 1 ng/mL, the DR and PPV were 69% and 85%, respectively, resulting in a CDR of 59%. There was a significant positive correlation between F-rhPSMA-7 PET/CT detection efficacy and stratified PSA levels ( = 0.005), as well as PSA nadir after prostatectomy ( < 0.001). F-rhPSMA-7 PET/CT offers high PPV in BCR after RP. Its CDR is dependent on the prescan PSA value with excellent CDR in patients with PSA ≥ 1 ng/mL.
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http://dx.doi.org/10.2967/jnumed.120.255661DOI Listing
July 2021

Joint Imaging Platform for Federated Clinical Data Analytics.

JCO Clin Cancer Inform 2020 11;4:1027-1038

German Cancer Consortium, Heidelberg, Germany.

Purpose: Image analysis is one of the most promising applications of artificial intelligence (AI) in health care, potentially improving prediction, diagnosis, and treatment of diseases. Although scientific advances in this area critically depend on the accessibility of large-volume and high-quality data, sharing data between institutions faces various ethical and legal constraints as well as organizational and technical obstacles.

Methods: The Joint Imaging Platform (JIP) of the German Cancer Consortium (DKTK) addresses these issues by providing federated data analysis technology in a secure and compliant way. Using the JIP, medical image data remain in the originator institutions, but analysis and AI algorithms are shared and jointly used. Common standards and interfaces to local systems ensure permanent data sovereignty of participating institutions.

Results: The JIP is established in the radiology and nuclear medicine departments of 10 university hospitals in Germany (DKTK partner sites). In multiple complementary use cases, we show that the platform fulfills all relevant requirements to serve as a foundation for multicenter medical imaging trials and research on large cohorts, including the harmonization and integration of data, interactive analysis, automatic analysis, federated machine learning, and extensibility and maintenance processes, which are elementary for the sustainability of such a platform.

Conclusion: The results demonstrate the feasibility of using the JIP as a federated data analytics platform in heterogeneous clinical information technology and software landscapes, solving an important bottleneck for the application of AI to large-scale clinical imaging data.
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http://dx.doi.org/10.1200/CCI.20.00045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713526PMC
November 2020

Regional Hyperthermia Enhances Mesenchymal Stem Cell Recruitment to Tumor Stroma: Implications for Mesenchymal Stem Cell-Based Tumor Therapy.

Mol Ther 2021 02 15;29(2):788-803. Epub 2020 Oct 15.

Department of Internal Medicine IV, University Hospital, LMU Munich, 81377 Munich, Germany; Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN, USA. Electronic address:

The tropism of mesenchymal stem cells (MSCs) for tumors forms the basis for their use as delivery vehicles for the tumor-specific transport of therapeutic genes, such as the theranostic sodium iodide symporter (NIS). Hyperthermia is used as an adjuvant for various tumor therapies and has been proposed to enhance leukocyte recruitment. Here, we describe the enhanced recruitment of adoptively applied NIS-expressing MSCs to tumors in response to regional hyperthermia. Hyperthermia (41°C, 1 h) of human hepatocellular carcinoma cells (HuH7) led to transiently increased production of immunomodulatory factors. MSCs showed enhanced chemotaxis to supernatants derived from heat-treated cells in a 3D live-cell tracking assay and was validated in vivo in subcutaneous HuH7 mouse xenografts. Cytomegalovirus (CMV)-NIS-MSCs were applied 6-48 h after or 24-48 h before hyperthermia treatment. Using I-scintigraphy, thermo-stimulation (41°C, 1 h) 24 h after CMV-NIS-MSC injection resulted in a significantly increased uptake of I in heat-treated tumors compared with controls. Immunohistochemical staining and real-time PCR confirmed tumor-selective, temperature-dependent MSC migration. Therapeutic efficacy was significantly enhanced by combining CMV-NIS-MSC-mediated I therapy with regional hyperthermia. We demonstrate here for the first time that hyperthermia can significantly boost tumoral MSC recruitment, thereby significantly enhancing therapeutic efficacy of MSC-mediated NIS gene therapy.
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http://dx.doi.org/10.1016/j.ymthe.2020.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854278PMC
February 2021

Lymphocyte Infiltration Determines the Hypoxia-Dependent Response to Definitive Chemoradiation in Head-and-Neck Cancer: Results from a Prospective Imaging Trial.

J Nucl Med 2021 04 28;62(4):471-478. Epub 2020 Aug 28.

Department of Radiation Oncology, Faculty of Medicine, Medical Center-University of Freiburg, University of Freiburg, Freiburg, Germany.

Tumor hypoxia in head-and-neck squamous cell carcinoma (HNSCC) leads to an immunosuppressive microenvironment and reduces the response to radiotherapy. In this prospective imaging trial, we investigated potential interactions between functional hypoxia imaging and infiltrating lymphocyte levels as a potential predictor for treatment response in HNSCC patients. In total, 49 patients receiving definitive chemoradiation for locally advanced HNSCCs underwent pretherapeutic biopsies and peritherapeutic hypoxia imaging using F-misonidazole PET at weeks 0, 2, and 5 during chemoradiation. Hematoxylin-eosin and immunohistochemical stainings for tumor-infiltrating lymphocytes, tissue-based hypoxia, and microvascular markers were analyzed and correlated with the longitudinal hypoxia dynamics and patient outcomes. High levels of tumor-infiltrating total lymphocytes correlated with superior locoregional control (LRC) (hazard ratio [HR], 0.279; = 0.011) and progression-free survival (PFS) (HR, 0.276; = 0.006). Similarly, early resolution of F-misonidazole PET-detected tumor hypoxia quantified by F-misonidazole dynamics between weeks 0 and 2 of chemoradiation was associated with improved LRC (HR, 0.321; = 0.015) and PFS (HR, 0.402; = 0.043). Outcomes in the favorable early hypoxia resolution subgroup significantly depended on infiltrating lymphocyte counts, with patients who showed both an early hypoxia response and high lymphocyte infiltration levels exhibiting significantly improved LRC (HR, 0.259; = 0.036) and PFS (HR, 0.242; = 0.017) compared with patients with an early hypoxia response but low lymphocyte counts. These patients exhibited oncologic results comparable to those of patients with no hypoxia response within the first 2 wk of chemoradiation. This analysis established a clinical hypoxia-immune score that predicted treatment responses and outcomes in HNSCC patients undergoing chemoradiation and may help to devise novel concepts for biology-driven personalization of chemoradiation.
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http://dx.doi.org/10.2967/jnumed.120.248633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049369PMC
April 2021
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