Publications by authors named "Wolfgang A Weber"

245 Publications

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

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

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

J Nucl Med 2021 Jan 30. Epub 2021 Jan 30.

Technical University of Munich, Department of Nuclear Medicine, Klinikum rechts der Isar; German Cancer Consortium (DKTK), partner-site Munich; and German Cancer Research Center (DKFZ) Heidelberg, Germany.

Blocking the interaction of the immune checkpoint molecules programmed cell death protein-1 (PD-1) and its ligand, PD-L1, using specific antibodies has been a major breakthrough for immune oncology. Whole-body PD-L1 expression positron emission tomography (PET) imaging may potentially allow for a better prediction of response to PD-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 labelling 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 carried out in NaOAc-buffer at pH 5.5 (50°C, 15min). In vitro stability in human serum at 37°C was analyzed using Radio-thin layer chromatography (Radio-TLC) and Radio-high performance liquid chromatography (Radio-HPLC). 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 negative control. Immunohistochemical staining studies, biodistribution and small animal PET studies of Ga-BMS-986192 were carried out using PD-L1-positive and negative U-698-M-bearing NSG mice. Ga-BMS-986192 was obtained with quantitative radiochemical yields (RCYs) >97% and with high radiochemical purity (RCP). In vitro stability in human serum was ≥ 95% after 4h 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 IHC staining. In vivo, Ga-BMS-986192 uptake was high in PD-L1+ tumors (9.0±2.1%ID/g at 1hp.i.) and kidneys (56.9±9.2% ID/g at 1hp.i.) with negligible uptake in other tissues. PD-L1 negative tumors demonstrated only background uptake of radioactivity (0.6±0.1% ID/g). Co-injection of an excess of unlabelled 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 demonstrate 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
January 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
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 Mar 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

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

Diagnostic Accuracy of F-PSMA-1007 PET/CT Imaging for Lymph Node Staging of Prostate Carcinoma in Primary and Biochemical Recurrence.

J Nucl Med 2021 02 17;62(2):208-213. Epub 2020 Aug 17.

Department of Nuclear Medicine, University Hospital, Heidelberg, Germany

Prostate-specific membrane antigen (PSMA)-ligand PET/CT is performed on patients with prostate cancer to stage the disease initially or to identify sites of recurrence after definitive therapy. On the basis of clinical results, F-PSMA-1007 is a promising PSMA PET tracer, but detailed histologic confirmation has been lacking. Ninety-six patients with prostate cancer underwent F-PSMA-1007 PET/CT followed by either radical prostatectomy with lymphadenectomy or salvage lymphadenectomy. The histologic findings of PSMA PET-positive nodes were analyzed retrospectively. A lesion-based and patient-based analysis was performed comparing all positive lesions and only lesions larger than 3 mm on histopathology. Of the patients, 90.6% received F-PSMA-1007 PET/CT for staging before the primary treatment, whereas 9.4% underwent imaging for biochemical recurrence. In 34.4% of the cohort, positive lymph nodes were present on imaging. In total, 1,746 lymph nodes were dissected in 96 patients. F-PSMA-1007 PET had a lesion-based sensitivity of 81.7%, a specificity of 99.6%, a positive predictive value of 92.4%, and a negative predictive value of 98.9% for detecting positive lymph nodes larger than 3 mm. In the analysis of all malignant nodes regardless of size, the overall sensitivity, specificity, positive predictive value, and negative predictive value on lesion-based analysis were 71.2%, 99.5%, 91.3%, and 97.9%, respectively. The patient-based analysis showed a sensitivity of 85.9% and a specificity of 99.5% for lymph nodes larger than 3 mm. F-PSMA-1007 PET/CT reliably detects malignant lymph nodes and has an exceptional specificity of more than 99% for nodal metastases.
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http://dx.doi.org/10.2967/jnumed.120.246363DOI Listing
February 2021

Hypoxia dynamics on FMISO-PET in combination with PD-1/PD-L1 expression has an impact on the clinical outcome of patients with Head-and-neck Squamous Cell Carcinoma undergoing Chemoradiation.

Theranostics 2020 23;10(20):9395-9406. Epub 2020 Jul 23.

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

Tumor-associated hypoxia influences the radiation response of head-and-neck cancer (HNSCC) patients, and a lack of early hypoxia resolution during treatment considerably deteriorates outcomes. As the detrimental effects of hypoxia are partly related to the induction of an immunosuppressive microenvironment, we investigated the interaction between tumor hypoxia dynamics and the PD-1/PD-L1 axis in HNSCC patients undergoing chemoradiation and its relevance for patient outcomes in a prospective trial. 49 patients treated with definitive chemoradiation for locally advanced HNSCC were enrolled in this trial and received longitudinal hypoxia PET imaging using fluorine-18 misonidazole ([F]FMISO) at weeks 0, 2 and 5 during treatment. Pre-therapeutic tumor biopsies were immunohistochemically analyzed regarding the PD-1/PD-L1 expression both on immune cells and on tumor cells, and potential correlations between the PD-1/PD-L1 axis and tumor hypoxia dynamics during chemoradiation were assessed using Spearman's rank correlations. Hypoxia dynamics during treatment were quantified by subtracting the standardized uptake value (SUV) index at baseline from the SUV values at weeks 2 or 5, whereby SUV index was defined as ratio of maximum tumor [F]FMISO SUV to mean SUV in the contralateral sternocleidomastoid muscle ( tumor-to-muscle ratio). The impact of the PD-1/PD-L1 expression alone and in combination with persistent tumor hypoxia on locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) was examined using log-rank tests and Cox proportional hazards models. Neither PD-L1 nor PD-1 expression levels on tumor-infiltrating immune cells influenced LRC (HR = 0.734; = 0.480 for PD-L1, HR = 0.991; = 0.989 for PD-1), PFS (HR = 0.813; = 0.597 for PD-L1, HR = 0.796; = 0.713 for PD-1) or OS (HR = 0.698; = 0.405 for PD-L1, HR = 0.315; = 0.265 for PD-1). However, patients with no hypoxia resolution between weeks 0 and 2 and PD-L1 expression on tumor cells, quantified by a tumor proportional score (TPS) of at least 1%, showed significantly worse LRC (HR = 3.374, = 0.022) and a trend towards reduced PFS (HR = 2.752, = 0.052). In the multivariate Cox regression analysis, the combination of absent tumor hypoxia resolution and high tumoral PD-L1 expression remained a significant prognosticator for impaired LRC (HR = 3.374, = 0.022). On the other side, tumoral PD-L1 expression did not compromise the outcomes of patients whose tumor-associated hypoxia declined between week 0 and 2 during chemoradiation (LRC: HR = 1.186, = 0.772, PFS: HR = 0.846, = 0.766). In this exploratory analysis, we showed for the first time that patients with both persistent tumor-associated hypoxia during treatment and PD-L1 expression on tumor cells exhibited a worse outcome, while the tumor cells' PD-L1 expression did not influence the outcomes of patients with early tumor hypoxia resolution. While the results have to be validated in an independent cohort, these findings form a foundation to investigate the combination of hypoxic modification and immune checkpoint inhibitors for the unfavorable subgroup, moving forward towards personalized radiation oncology treatment.
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http://dx.doi.org/10.7150/thno.48392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415814PMC
July 2020

Almost 10 years of PET/MR attenuation correction: the effect on lesion quantification with PSMA: clinical evaluation on 200 prostate cancer patients.

Eur J Nucl Med Mol Imaging 2021 Feb 28;48(2):543-553. Epub 2020 Jul 28.

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

Purpose: After a decade of PET/MR, the case of attenuation correction (AC) remains open. The initial four-compartment (air, water, fat, soft tissue) Dixon-based AC scheme has since been expanded with several features, the latest being MR field-of-view extension and a bone atlas. As this potentially changes quantification, we evaluated the impact of these features in PET AC in prostate cancer patients.

Methods: Two hundred prostate cancer patients were examined with either F- or Ga-prostate-specific membrane antigen (PSMA) PET/MR. Qualitative and quantitative analysis (SUV, SUV, correlation, and statistical significance) was performed on images reconstructed using different AC schemes: Dixon, Dixon+MLAA, Dixon+HUGE, and Dixon+HUGE+bones for F-PSMA data; Dixon and Dixon+bones for Ga-PSMA data. Uptakes were compared using linear regression against standard Dixon.

Results: High correlation and no visually perceivable differences between all evaluated methods (r > 0.996) were found. The mean relative difference in lesion uptake of F-PSMA and Ga-PSMA remained, respectively, within 4% and 3% in soft tissue, and within 10% and 9% in bones for all evaluated methods. Bone registration errors were detected, causing mean uptake change of 5% in affected lesions.

Conclusions: Based on these results and the encountered bone atlas registration inaccuracy, we deduce that including bones and extending the MR field-of-view did not introduce clinically significant differences in PSMA diagnostic accuracy and tracer uptake quantification in prostate cancer pelvic lesions, facilitating the analysis of serial studies respectively. However, in the absence of ground truth data, we advise against atlas-based methods when comparing serial scans for bone lesions.
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http://dx.doi.org/10.1007/s00259-020-04957-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835314PMC
February 2021

Effect of Tumor Perfusion and Receptor Density on Tumor Control Probability in Lu-DOTATATE Therapy: An In Silico Analysis for Standard and Optimized Treatment.

J Nucl Med 2021 01 9;62(1):92-98. Epub 2020 Jul 9.

Department of Nuclear Medicine, Ulm University, Ulm, Germany

The aim of this work was to determine a minimal tumor perfusion and receptor density for Lu-DOTATATE therapy using physiologically based pharmacokinetic (PBPK) modeling considering, first, a desired tumor control probability (TCP) of 99% and, second, a maximal tolerated biologically effective dose (BED) for organs at risk (OARs) in the treatment of neuroendocrine tumors and meningioma. A recently developed PBPK model was used. Nine virtual patients (i.e., individualized PBPK models) were used to perform simulations of pharmacokinetics for different combinations of perfusion (0.001-0.1 mL/g/min) and receptor density (1-100 nmol/L). The TCP for each combination was determined for 3 different treatment strategies: a standard treatment (4 cycles of 7.4 GBq and 105 nmol), a treatment maximizing the number of cycles based on BED for red marrow and kidneys, and a treatment having 4 cycles with optimized ligand amount and activity. The red marrow and the kidneys (BED of 2 Gy and 40 Gy, respectively) were assumed to be OARs. Additionally, the influence of varying glomerular filtration rates, kidney somatostatin receptor densities, tumor volumes, and release rates was investigated. To achieve a TCP of at least 99% in the standard treatment, a minimal tumor perfusion of 0.036 ± 0.023 mL/g/min and receptor density of 34 ± 20 nmol/L were determined for the 9 virtual patients. With optimization of the number of cycles, the minimum values for perfusion and receptor density were considerably lower, at 0.022 ± 0.012 mL/g/min and 21 ± 11 nmol/L, respectively. However, even better results (perfusion, 0.018 ± 0.009 mL/g/min; receptor density, 18 ± 10 nmol/L) were obtained for strategy 3. The release rate of Lu (or labeled metabolites) from tumor cells had the strongest effect on the minimal perfusion and receptor density for standard and optimized treatments. PBPK modeling and simulations represent an elegant approach to individually determine the minimal tumor perfusion and minimal receptor density required to achieve an adequate TCP. This computational method can be used in the radiopharmaceutical development process for ligand and target selection for specific types of tumors. In addition, this method could be used to optimize clinical trials.
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http://dx.doi.org/10.2967/jnumed.120.245068DOI Listing
January 2021

Efficacy and Safety of Lu-labeled Prostate-specific Membrane Antigen Radionuclide Treatment in Patients with Diffuse Bone Marrow Involvement: A Multicenter Retrospective Study.

Eur Urol 2020 08 10;78(2):148-154. Epub 2020 Jun 10.

Department of Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

The Lu-labeled prostate-specific membrane antigen (LuPSMA) radionuclide therapy for metastatic castration-resistant prostate cancer is under investigation in a phase III trial (VISION: NCT03511664). However, patients with diffuse bone involvement, diagnosed with a "superscan" by bone scintigraphy at baseline, were excluded due to a lack of efficacy and safety data. We therefore aimed to investigate the feasibility of LuPSMA in patients with diffuse bone marrow involvement on baseline PSMA-targeted positron emission tomography. The primary end points were prostate-specific antigen (PSA) response (Prostate Cancer Working Group 3 [PCWG3]), hematologic safety profile (Common Terminology Criteria for Common Adverse Events [CTCAE]), and overall survival. Secondary end points of quality of life (assessed with Brief Pain Inventory-Short Form questionnaires) and radiologic response (Response Evaluation Criteria in Solid Tumors [RECIST]) were assessed. Through retrospective screening of databases, we identified 43 eligible patients across four centers worldwide who received 154 cycles of LuPSMA under clinical trials or compassionate access programs. Median baseline PSA was 1000 (interquartile range 431-2151) ng/ml. PSA decline of at least 50% at 12 wk was achieved in 22 (58%) patients, while median time to pain progression was 8.3 (95% confidence interval [CI] 4.1-12.6) mo. Median overall survival was 11.6 (95% CI 8.8-14.3) mo. Objective response in nodal or visceral disease was reported in seven (39%) of 18 patients with RECIST measurable disease. Grade 3 anemia, thrombocytopenia, and neutropenia occurred in nine (22%), seven (17%), and three (8%) patients, respectively. Grade 4 thrombocytopenia was noticed in three (8%) patients. In conclusion, patients with diffuse bone marrow involvement demonstrated similar LuPSMA efficacy and safety to phase II evidence. Acceptable safety outcomes do not support exclusion of patients with a superscan from future LuPSMA treatment protocols. PATIENT SUMMARY: In this report, we investigated the feasibility of prostate-specific membrane antigen (PSMA)-directed radionuclide treatment in patients with metastatic castration-resistant prostate cancer and diffuse bone involvement. We found that, despite a high load of bone metastases, PSMA-targeted therapy remains efficacious and safe when compared with the current phase II trial results.
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http://dx.doi.org/10.1016/j.eururo.2020.05.004DOI Listing
August 2020

Comparison of Ga-DOTA-JR11 PET/CT with dosimetric Lu-satoreotide tetraxetan (Lu-DOTA-JR11) SPECT/CT in patients with metastatic neuroendocrine tumors undergoing peptide receptor radionuclide therapy.

Eur J Nucl Med Mol Imaging 2020 12 6;47(13):3047-3057. Epub 2020 May 6.

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

Purpose: Paired imaging/therapy with radiolabeled somatostatin receptor (SSTR) antagonists is a novel approach in neuroendocrine tumors (NETs). The aim of this study was to compare tumor uptake of Ga-DOTA-JR11 and Lu-satoreotide tetraxetan (Lu-DOTA-JR11) in patients with NETs.

Methods: As part of a prospective clinical trial, 20 patients with metastatic NETs underwent Ga-DOTA-JR11 PET/CT and serial imaging with Lu-satoreotide tetraxetan. PET/CT and SPECT/CT parameters for lesion uptake and absorbed dose of Lu-satoreotide tetraxetan in lesions were compared using linear regression analysis and Pearson correlation.

Results: A total of 95 lesions were analyzed on Ga-DOTA-JR11 PET/CT and Lu-satoreotide tetraxetan SPECT/CT. SUVs and tumor-to-normal-tissue ratios on PET/CT and SPECT/CT were significantly correlated (p < 0.01), but the degree of correlation was modest with Pearson correlation coefficients ranging from 0.3 to 0.7. Variation in intrapatient lesional correlation was observed. Nevertheless, in all patients, the lesion SUVpeak uptake ratio for Lu-satoreotide tetraxetan vs. Ga-DOTA-JR11 was high; even in those with low uptake on Ga-DOTA-JR11 PET/CT (SUVpeak ≤ 10), a ratio of 8.0 ± 5.2 was noted. Correlation of SUVpeak of Ga-DOTA-JR11 with projected Lu-satoreotide tetratexan-absorbed dose (n = 42) was modest (r = 0.5, p < 0.01), while excellent correlation of SUVpeak of Lu-satoreotide tetraxetan with projected Lu-satoreotide tetraxetan-absorbed dose was noted (r = 0.9, p < 0.0001).

Conclusion: Our study shows that Ga-DOTA-JR11 PET can be used for patient selection and PRRT and that low tumor uptake on PET should not preclude patients from treatment with Lu-satoreotide tetraxetan. The ability to use single time-point SPECT/CT for absorbed dose calculations could facilitate dosimetry regimens, save costs, and improve patient convenience.
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http://dx.doi.org/10.1007/s00259-020-04832-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644587PMC
December 2020

Effective control of tumor growth through spatial and temporal control of theranostic sodium iodide symporter () gene expression using a heat-inducible gene promoter in engineered mesenchymal stem cells.

Theranostics 2020 15;10(10):4490-4506. Epub 2020 Mar 15.

Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany.

: The tumor homing characteristics of mesenchymal stem cells (MSCs) make them attractive vehicles for the tumor-specific delivery of therapeutic agents, such as the sodium iodide symporter (NIS). NIS is a theranostic protein that allows non-invasive monitoring of the biodistribution of functional NIS expression by radioiodine imaging as well as the therapeutic application of I. To gain local and temporal control of transgene expression, and thereby improve tumor selectivity, we engineered MSCs to express the gene under control of a heat-inducible HSP70B promoter (HSP70B-NIS-MSCs). : NIS induction in heat-treated HSP70B-NIS-MSCs was verified by I uptake assay, RT-PCR, Western blot and immunofluorescence staining. HSP70B-NIS-MSCs were then injected i.v. into mice carrying subcutaneous hepatocellular carcinoma HuH7 xenografts, and hyperthermia (1 h at 41°C) was locally applied to the tumor. 0 - 72 h later radioiodine uptake was assessed by I-scintigraphy. The most effective uptake regime was then selected for I therapy. : The HSP70B promoter showed low basal activity and was significantly induced in response to heat. , the highest tumoral iodine accumulation was seen 12 h after application of hyperthermia. HSP70B-NIS-MSC-mediated I therapy combined with hyperthermia resulted in a significantly reduced tumor growth with prolonged survival as compared to control groups. : The heat-inducible HSP70B promoter allows hyperthermia-induced spatial and temporal control of MSC-mediated theranostic gene radiotherapy with efficient tumor-selective and temperature-dependent accumulation of radioiodine in heat-treated tumors.
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http://dx.doi.org/10.7150/thno.41489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150485PMC
April 2021

Development of a Chimeric Antigen-Binding Fragment Directed Against Human Galectin-3 and Validation as an Immuno-Positron Emission Tomography Tracer for the Sensitive Imaging of Thyroid Cancer.

Thyroid 2020 09 30;30(9):1314-1326. Epub 2020 Apr 30.

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

The lack of facile methods for the specific characterization of malignant thyroid nodules makes the diagnosis of thyroid cancer (TC) challenging. Due to its restricted expression in such nodules, the cell-associated lectin galectin-3 (Gal3) has emerged as a marker for TC with growing interest for imaging as well as targeted radionuclide therapy. To accelerate translation into clinical application, we have developed a cognate chimeric human antigen-binding fragment (Fab) derived from the rat anti-Gal3 monoclonal antibody M3/38. The variable immunoglobulin (Ig) light and heavy chain sequences were cloned from the hybridoma cell line, and the corresponding Fab carrying human IgG1/κ constant genes was functionally produced in the periplasm of and purified to homogeneity. To moderately prolong its plasma half-life and, thus, increase tumor uptake, the recombinant Fab was fused with a long disordered amino acid chain comprising in total 200 Pro, Ala, and Ser residues (PASylation). This novel tracer was subjected to characterization and validation by using two thyroid cancer orthotopic murine models. To this end, the αGal3-Fab-PAS was conjugated with deferoxamine (Dfo), labeled with Zr under mild conditions and tested for binding on TC cell lines. Athymic nude mice were inoculated either with FRO82-1 or with CAL62 tumor cells into the left thyroid lobe. After intravenous injection with ∼3.0 MBq of Zr-Dfo-PAS-Fab, these mice were subjected to positron emission tomography (PET)/computed tomography imaging followed by quantification of tumor accumulation and immunohistochemical analysis. The αGal3-Fab-PAS revealed high affinity toward the recombinant Gal3 antigen, with a dissociation constant ≤1 nM as measured via enzyme-linked immunosorbent assay, surface plasmon resonance spectroscopy, and radioactive cell binding assay. The Gal3-targeting by the Zr(IV)-labeled protein tracer, as investigated by immuno-PET, demonstrated highly selective and fast accumulation in orthotopically implanted tumors, with strong contrast images achieved 24 hours postinjection, and no uptake in the tumor-free thyroid lobe, as also confirmed by biodistribution studies. The chimeric αGal3 Zr-Dfo-PAS-Fab tracer exhibits selective accumulation in the tumor-bearing thyroid lobe of xenograft mice. Thus, this novel radioactive probe offers potential to change TC management, in addition to current diagnostic procedures, and to reduce unnecessary thyroidectomies.
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http://dx.doi.org/10.1089/thy.2019.0670DOI Listing
September 2020

First-in-Humans Trial of Dasatinib-Derivative Tracer for Tumor Kinase-Targeted PET.

J Nucl Med 2020 11 13;61(11):1580-1587. Epub 2020 Mar 13.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York

We developed a first-of-kind dasatinib-derivative imaging agent, F-SKI-249380 (F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assessed the feasibility of using F-SKI for PET imaging in patients with malignancies. Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min after injection of F-SKI (mean, 241.24 ± 116.36 MBq) as part of a prospective study. In addition, patients underwent either a 30-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney ( = 2) or three 10-min whole-body PET/CT scans ( = 3) immediately after injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of 3 patients had a delayed whole-body PET/CT scan at 180 min. Biodistribution, dosimetry, and tumor uptake were quantified. Absorbed doses were calculated using OLINDA/EXM 1.0. No adverse events occurred after injection of F-SKI. In total, 27 tumor lesions were analyzed, with a median SUV of 1.4 (range, 0.7-2.3) and tumor-to-blood ratios of 1.6 (range, 0.8-2.5) at 90 min after injection. The intratumoral drug concentrations calculated for 4 reference lesions ranged from 0.03 to 0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30 and 90 min after injection. A blood radioassay indicated that radiotracer clearance from blood and plasma was initially rapid (blood half-time, 1.31 ± 0.81 min; plasma, 1.07 ± 0.66 min; = 4), followed variably by either a prolonged terminal phase (blood half-time, 285 ± 148.49 min; plasma, 240 ± 84.85 min; = 2) or a small rise to a plateau ( = 2). Like dasatinib, F-SKI underwent extensive metabolism after administration, as evidenced by metabolite analysis. Radioactivity was predominantly cleared via the hepatobiliary route. The highest absorbed dose estimates (mGy/MBq) in normal tissues were to the right colon (0.167 ± 0.04) and small intestine (0.153 ± 0.03). The effective dose was 0.0258 mSv/MBq (SD, 0.0034 mSv/MBq). F-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood.
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http://dx.doi.org/10.2967/jnumed.119.234864DOI Listing
November 2020

Early Prostate-Specific Antigen Changes and Clinical Outcome After Lu-PSMA Radionuclide Treatment in Patients with Metastatic Castration-Resistant Prostate Cancer.

J Nucl Med 2020 10 28;61(10):1476-1483. Epub 2020 Feb 28.

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

Prostate-specific antigen (PSA) is widely used to monitor treatment response in patients with metastatic castration-resistant prostate cancer. However, PSA measurements are considered only after 12 wk of treatment. We aimed to evaluate the prognostic value of early PSA changes after Lu-labeled prostate-specific membrane antigen (Lu-PSMA) radionuclide treatment in metastatic castration-resistant prostate cancer patients. Men who were treated with Lu-PSMA under a compassionate-access program at our institution and had available PSA values at baseline and at 6 wk after treatment initiation were included in this retrospective analysis. Patients were assigned to 3 groups on the basis of PSA changes: response (≥30% decline), progression (≥25% increase), and stable (<30% decline and <25% increase). The coprimary endpoints were overall survival and imaging-based progression-free survival. The secondary endpoints were PSA changes at 12 wk and PSA flare-up. We identified 124 eligible patients with PSA values at 6 wk. A greater than or equal to 30% decline in PSA at 6 wk was associated with longer overall survival (median, 16.7 mo; 95% CI, 14.4-19.0) than stable PSA (median, 11.8 mo; 95% CI, 8.6-15.1) ( = 0.007) or PSA progression (median, 6.5 mo; 95% CI, 5.2-7.8) ( < 0.001). Patients with a greater than or equal to 30% decline in PSA at 6 wk also had a lower risk of imaging-based progression than patients with stable PSA (hazard ratio, 0.60; 95% CI, 0.38-0.94) ( = 0.02), whereas patients with PSA progression had a higher risk of imaging-based progression than patients with stable PSA (hazard ratio, 3.18; 95% CI, 1.95-5.21) ( < 0.001). The percentage changes in PSA at 6 and 12 wk were highly associated ( = 0.90; < 0.001). Of 31 patients who experienced early PSA progression at 6 wk, 29 (94%) showed biochemical progression at 12 wk. Overall, only 1 (3%) of 36 patients with PSA progression at 6 wk achieved any PSA decline at 12 wk (1% of the entire cohort). The limitations of the study included its retrospective nature and the single-center experience. PSA changes at 6 wk after Lu-PSMA initiation are an early indicator of long-term clinical outcome. Patients with PSA progression after 6 wk of treatment could benefit from a very early decision to switch treatment. PSA flare-up during Lu-PSMA treatment is very uncommon. Prospective studies are now warranted to validate our findings and potentially inform clinicians earlier on the effectiveness of Lu-PSMA.
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http://dx.doi.org/10.2967/jnumed.119.240242DOI Listing
October 2020

Pre-test Ga-PSMA-ligand PET/CT positivity in early biochemical recurrent prostate cancer after radical prostatectomy-validation of a prediction model.

EJNMMI Res 2020 Feb 3;10(1). Epub 2020 Feb 3.

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

Objectives: The aim of this study was the validation of a recently established comprehensive and compact prediction model for Ga-PSMA-11-ligand positron-emission tomography (PET) positivity with an independent subsequent patient series.

Methods: A total of 292 consecutive patients with early biochemical recurrence after radical prostatectomy and PSA values between 0.2 and 1 ng/ml who underwent Ga-PSMA-11-ligand PET/computed tomography (CT) between January 2016 and June 2017 were retrospectively included. The cohort was divided into a very low PSA value (0.2-0.5 ng/ml, n = 151) and a low PSA value (> 0.5-1 ng/ml, n = 141) subgroup. First, pre-test positivity probabilities for each patient were calculated according to the previously published comprehensive prediction model using all clinical variables (PSA value, ISUP grade group, T- and N-stage, patient under androgen deprivation therapy (ADT), previous radiation therapy) and the compact model using just the most predictive factors PSA value, ADT, and grade group. Then, all Ga-PSMA-11-ligand PET/CTs were analysed by one experienced nuclear medicine physician, and the results were correlated to the calculated pre-test probabilities.

Results: In the very low PSA value subgroup, mean pre-test probability for positive findings in Ga-PSMA-11-ligand PET/CT was 57% (95% CI 55-60%) according to the compact model and 59% (95% CI 56-61%) according to the comprehensive model. In the low PSA value subgroup, mean pre-test probability was 72% (95% CI 70-74%) in the compact model and 74% (95% CI 72-76%) in the comprehensive model. After image analysis, 59% (89/151) of the patients in the very low PSA value subgroup revealed positive imaging findings. Seventy-nine percent (112/141) of the patients in the low PSA value subgroup presented with positive findings in the Ga-PSMA-11-ligand PET/CT. The accuracy (AUC) of the prediction models was 0.71 (95% CI 0.65-0.78) for the compact model and 0.74 (95% CI 0.68-0.80) for the comprehensive model.

Conclusion: External validation of the recently proposed prediction models showed a high concordance of the calculated pre-test probabilities and actual Ga-PSMA-11-ligand PET/CT findings in the validation cohort confirming the prediction models' ability to determine the presence of a positive lesion at Ga-PSMA-11-ligand PET. However, the predictive accuracy of the nomogram itself is suboptimal and should be used with caution. Furthermore, the model's generalizability may be hampered due to the study design (in-house validation). Nevertheless, given the limited health resources and the costs of hybrid imaging techniques, prediction models might be a benefit in patient selection.
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http://dx.doi.org/10.1186/s13550-020-0595-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997317PMC
February 2020

The AQARA Principle: Proposing Standard Requirements for Radionuclide-Based Images in Medical Journals.

J Nucl Med 2020 01;61(1):1-2

Memorial Sloan Kettering Cancer Center, New York, New York.

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http://dx.doi.org/10.2967/jnumed.119.240523DOI Listing
January 2020

C-Choline PET/CT in Recurrent Prostate Cancer: Retrospective Analysis in a Large U.S. Patient Series.

J Nucl Med 2020 06 20;61(6):827-833. Epub 2019 Dec 20.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York

Our purpose was to evaluate the performance of C-choline PET/CT in detecting biochemically recurrent prostate cancer (PCa) in a large non-European cohort (in the context of emerging evidence for prostate-specific membrane antigen PET in this setting) and to map patterns of PCa recurrence. We retrospectively analyzed C-choline PET/CT scans from 287 patients who were enrolled in an imaging protocol based on rising prostate-specific antigen (PSA) levels (mean, 3.43 ng/mL; median, 0.94 ng/mL; range, 0.15-89.91 ng/mL) and suspected recurrent PCa. A total of 187 patients had undergone primary radical prostatectomy (RP) (79/187 had secondary radiotherapy), 30 had undergone primary radiotherapy, and 70 had a persistent PSA elevation after receiving initial treatment (69 after RP, 1 after radiotherapy). The level of suspicion for recurrence on C-choline PET/CT was scored (0, negative; 1, equivocal; 2, positive) by 2 readers. The correlation between C-choline PET/CT positivity and initial treatment, Gleason score, National Comprehensive Cancer Network stage, PSA level, PSA doubling time, PSA velocity, and time between initial treatment and PET imaging was evaluated. Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria were used to map C-choline recurrence patterns. Considering scores 1 and 2 as positives, consensus between the 2 readers deemed 66% of the C-choline PET/CT scans as positive. When sorted by PSA level, 45% of patients with a PSA of less than 0.5 ng/mL, 56% of patients with a PSA of 0.5-0.99 ng/mL, 70% of patients with a PSA of 1.0-1.99 ng/mL, and 90% of patients with a PSA of at least 2.0 ng/mL scored either 1 or 2 on C-choline PET/CT scans. When considering scores of 2 only, C-choline PET/CT positivity was 54% (28%, 46%, 62%, and 81%, respectively, for patients with PSA < 0.5 ng/mL, 0.5-0.99 ng/mL, 1.0-1.99 ng/mL, and ≥ 2.0 ng/mL). In multivariate analysis, only PSA level was significantly associated with scan positivity. Pattern analysis showed that pelvic lymph nodes were the most common site of recurrence, and 28% of patients had C-choline-positive suspected recurrences outside the initial treatment field. C-choline PET/CT can detect PCa recurrence even among patients with low PSA levels when interpretation accounts for the clinical context, providing a certain pretest probability. Until prostate-specific membrane antigen agents are fully approved for PCa, choline PET/CT may provide clinical utility.
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http://dx.doi.org/10.2967/jnumed.119.233098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262219PMC
June 2020

Quantitative and Qualitative Analyses of Biodistribution and PET Image Quality of a Novel Radiohybrid PSMA, F-rhPSMA-7, in Patients with Prostate Cancer.

J Nucl Med 2020 05 13;61(5):702-709. Epub 2019 Dec 13.

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

Radiohybrid PSMA (rhPSMA) ligands, a new class of theranostic prostate-specific membrane antigen (PSMA)-targeting agents, feature fast F synthesis and utility for labeling with radiometals. Here, we assessed the biodistribution and image quality of F-rhPSMA-7 to determine the best imaging time point for patients with prostate cancer. In total, 202 prostate cancer patients who underwent a clinically indicated F-rhPSMA-7 PET/CT were retrospectively analyzed, and 12 groups based on the administered activity and uptake time of PET scanning were created: 3 administered activities (low, 222-296 MBq; moderate, 297-370 MBq; and high, 371-444 MBq) and 4 uptake time points (short, 50-70 min; intermediate, 71-90 min; long, 91-110 min; and extra long, ≥111 min). For quantitative analyses, SUV and organ- or tumor-to-background ratio were determined for background, healthy organs, and 3 representative tumor lesions. Qualitative analyses assessed overall image quality, nonspecific blood-pool activity, and background uptake in bone or marrow using 3- or 4-point scales. In quantitative analyses, SUV showed a significant decrease in the blood pool and lungs and an increase in the kidneys, bladder, and bones as the uptake time increased. SUV showed a trend to increase in the blood pool and bones as the administered activity increased. However, no significant differences were found in 377 tumor lesions with respect to the administered activity or uptake time. In qualitative analyses, the overall image quality was stable along with the uptake time, but the proportion rated to have good image quality decreased as the administered activity increased. All other qualitative image parameters showed no significant differences for the administered activities, but they showed significant trends with increasing uptake time: less nonspecific blood activity, more frequent background uptake in the bone marrow, and increased negative impact on clinical decision making. The biodistribution of F-rhPSMA-7 was similar to that of established PSMA ligands, and tumor uptake of F-rhPSMA-7 was stable across the administered activities and uptake times. An early imaging time point (50-70 min) is recommended for F-rhPSMA-7 PET/CT to achieve the highest overall image quality.
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http://dx.doi.org/10.2967/jnumed.119.234609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198378PMC
May 2020

Histologically Confirmed Diagnostic Efficacy of F-rhPSMA-7 PET for N-Staging of Patients with Primary High-Risk Prostate Cancer.

J Nucl Med 2020 05 13;61(5):710-715. Epub 2019 Dec 13.

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

F-rhPSMA-7 (radiohybrid prostate-specific membrane antigen [PSMA]) is a novel ligand for PET imaging. Here, we present data from a retrospective analysis using PET/CT and PET/MRI examinations to investigate the efficacy of F-rhPSMA-7 PET for primary N-staging of patients with prostate cancer (PC) compared with morphologic imaging (CT or MRI) and validated by histopathology. Data from 58 patients with high-risk PC (according to the D'Amico criteria) who were staged with F-rhPSMA-7 PET/CT or PET/MRI at our institution between July 2017 and June 2018 were reviewed. The patients had a median prescan prostate-specific antigen value of 12.2 ng/mL (range, 1.2-81.6 ng/mL). The median injected activity of F-rhPSMA-7 was 327 MBq (range, 132-410 MBq), with a median uptake time of 79.5 min (range, 60-153 min). All patients underwent subsequent radical prostatectomy and extended pelvic lymph node dissection. The presence of lymph node metastases was determined by an experienced reader independently for both the PET and the morphologic datasets using a template-based analysis on a 5-point scale. Patient-level and template-based results were both compared with histopathologic findings. Lymph node metastases were present in 18 patients (31.0%) and were located in 52 of 375 templates (13.9%). Receiver-operating-characteristic analyses showed F-rhPSMA-7 PET to perform significantly better than morphologic imaging on both patient-based and template-based analyses (areas under curve, 0.858 vs. 0.649 [ = 0.012] and 0.765 vs. 0.589 [ < 0.001], respectively). On patient-based analyses, the sensitivity, specificity, and accuracy of F-rhPSMA-7 PET were 72.2%, 92.5%, and 86.2%, respectively, and those of morphologic imaging were 50.0%, 72.5%, and 65.5%, respectively. On template-based analyses, the sensitivity, specificity, and accuracy of F-rhPSMA-7 PET were 53.8%, 96.9%, and 90.9%, respectively, and those of morphologic imaging were 9.6%, 95.0%, and 83.2%, respectively. F-rhPSMA-7 PET is superior to morphologic imaging for N-staging of high-risk primary PC. The efficacy of F-rhPSMA-7 is similar to published data for Ga-PSMA-11.
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http://dx.doi.org/10.2967/jnumed.119.234906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198390PMC
May 2020

Correlative analyses between tissue-based hypoxia biomarkers and hypoxia PET imaging in head and neck cancer patients during radiochemotherapy-results from a prospective trial.

Eur J Nucl Med Mol Imaging 2020 05 7;47(5):1046-1055. Epub 2019 Dec 7.

German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Purpose: Tumor hypoxia impairs the response of head-and-neck cancer (HNSCC) patients to radiotherapy and can be detected both by tissue biomarkers and PET imaging. However, the value of hypoxia biomarkers and imaging for predicting HNSCC patient outcomes are incompletely understood, and potential correlations between tissue and PET data remain to be elucidated. Here, we performed exploratory analyses of potential correlations between tissue-based hypoxia biomarkers and longitudinal hypoxia imaging in a prospective trial of HNSCC patients.

Methods: Forty-nine patients undergoing chemoradiation for locally advanced HNSCCs were enrolled in this prospective trial. They underwent baseline biopsies and [F]FDG PET imaging and [F]FMISO PET at weeks 0, 2, and 5 during treatment. Immunohistochemical analyses for p16, Ki67, CD34, HIF1α, CAIX, Ku80, and CD44 were performed, and HPV status was assessed. Biomarker expression was correlated with biological imaging information and patient outcome data.

Results: High HIF1α tumor levels significantly correlated with increased tumor hypoxia at week 2 as assessed by the difference in the [F]FMISO tumor-to-background ratios, and high HIF1α and CAIX expressions were both associated with a deferred decrease in hypoxia between weeks 2 and 5. Loco-regional recurrence rates after radiotherapy were significantly higher in patients with high CAIX expression and also increased for high levels of the DNA repair factor Ku80. HPV status did not correlate with any of the tested hypoxia biomarkers, and HPV-positive patients showed higher loco-regional control rates and progression-free survival independent of their hypoxia dynamics.

Conclusion: In this exploratory trial, high expression of the tissue-based hypoxia biomarkers HIF1α and CAIX correlated with adverse hypoxia dynamics in HNSCCs during chemoradiation as assessed by PET imaging, and high CAIX levels were associated with increased loco-regional recurrence rates. Hence, hypoxia biomarkers warrant further investigations as potential predictors of hypoxia dynamics and hypoxia-associated radiation resistance.
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http://dx.doi.org/10.1007/s00259-019-04598-9DOI Listing
May 2020

Evaluation of SUV normalized by lean body mass (SUL) in Ga-PSMA11 PET/CT: a bi-centric analysis.

EJNMMI Res 2019 Dec 2;9(1):103. Epub 2019 Dec 2.

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

Introduction: The aim of this analysis was to investigate whether the standardized uptake value (SUV) normalized by lean body mass (SUL) is a more appropriate quantitative parameter compared to the commonly used SUV normalized by patient's weight in Ga-PSMA11 PET/CT.

Material And Methods: Ga-PSMA11 PET/CT scans of 121 patients with prostate cancer from two institutions were evaluated. Liver SUV was measured within a 3-cm volume-of-interest (VOI) in the right hepatic lobe and corrected for lean body mass using the Janmahasatian formula. SUV and SUL repeatability between baseline and follow-up scans of the same patients were assessed.

Results: SUV was significantly positively correlated with body weight (r = 0.35, p = 0.02). In contrast, SUL was not correlated with body weight (r = 0.23, p = 0.07). No significant differences were found between baseline and follow-up scan (p = 0.52).

Conclusion: The Janmahasatian formula annuls the positive correlations between SUV and body weight, suggesting that SUL is preferable to SUV for quantitative analyses of Ga-PSMA11 PET/CT scans.
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http://dx.doi.org/10.1186/s13550-019-0572-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889088PMC
December 2019

First-in-Humans Imaging with Zr-Df-IAB22M2C Anti-CD8 Minibody in Patients with Solid Malignancies: Preliminary Pharmacokinetics, Biodistribution, and Lesion Targeting.

J Nucl Med 2020 04 4;61(4):512-519. Epub 2019 Oct 4.

Department of Medicine, Weill Cornell Medical College, New York, New York.

Immunotherapy is becoming the mainstay for treatment of a variety of malignancies, but only a subset of patients responds to treatment. Tumor-infiltrating CD8-positive (CD8+) T lymphocytes play a central role in antitumor immune responses. Noninvasive imaging of CD8+ T cells may provide new insights into the mechanisms of immunotherapy and potentially predict treatment response. We are studying the safety and utility of Zr-IAB22M2C, a radiolabeled minibody against CD8+ T cells, for targeted imaging of CD8+ T cells in patients with cancer. The initial dose escalation phase of this first-in-humans prospective study included 6 patients (melanoma, 1; lung, 4; hepatocellular carcinoma, 1). Patients received approximately 111 MBq (3 mCi) of Zr-IAB22M2C (at minibody mass doses of 0.2, 0.5, 1.0, 1.5, 5, or 10 mg) as a single dose, followed by PET/CT scans at approximately 1-2, 6-8, 24, 48, and 96-144 h after injection. Biodistribution in normal organs, lymph nodes, and lesions was evaluated. In addition, serum samples were obtained at approximately 5, 30, and 60 min and later at the times of imaging. Patients were monitored for safety during infusion and up to the last imaging time point. Zr-IAB22M2C infusion was well tolerated, with no immediate or delayed side effects observed after injection. Serum clearance was typically biexponential and dependent on the mass of minibody administered. Areas under the serum time-activity curve, normalized to administered activity, ranged from 1.3 h/L for 0.2 mg to 8.9 h/L for 10 mg. Biodistribution was dependent on the minibody mass administered. The highest uptake was always in spleen, followed by bone marrow. Liver uptake was more pronounced with higher minibody masses. Kidney uptake was typically low. Prominent uptake was seen in multiple normal lymph nodes as early as 2 h after injection, peaking by 24-48 h after injection. Uptake in tumor lesions was seen on imaging as early as 2 h after injection, with most Zr-IAB22M2C-positive lesions detectable by 24 h. Lesions were visualized early in patients receiving treatment, with SUV ranging from 5.85 to 22.8 in 6 target lesions. Zr-IAB22M2C imaging is safe and has favorable kinetics for early imaging. Biodistribution suggests successful targeting of CD8+ T-cell-rich tissues. The observed targeting of tumor lesions suggests this may be informative for CD8+ T-cell accumulation within tumors. Further evaluation is under way.
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http://dx.doi.org/10.2967/jnumed.119.229781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198374PMC
April 2020

Retooling a Blood-Based Biomarker: Phase I Assessment of the High-Affinity CA19-9 Antibody HuMab-5B1 for Immuno-PET Imaging of Pancreatic Cancer.

Clin Cancer Res 2019 12 20;25(23):7014-7023. Epub 2019 Sep 20.

Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: In patients with cancer who have an abnormal biomarker finding, the source of the biomarker in the bloodstream must be located for confirmation of diagnosis, staging, and therapy planning. We evaluated if immuno-PET with the radiolabeled high-affinity antibody HuMab-5B1 (MVT-2163), binding to the cancer antigen CA19-9, can identify the source of elevated biomarkers in patients with pancreatic cancer.

Patients And Methods: In this phase I dose-escalating study, 12 patients with CA19-9-positive metastatic malignancies were injected with MVT-2163. Within 7 days, all patients underwent a total of four whole-body PET/CT scans. A diagnostic CT scan was performed prior to injection of MVT-2163 to correlate findings on MVT-2163 PET/CT.

Results: Immuno-PET with MVT-2163 was safe and visualized known primary tumors and metastases with high contrast. In addition, radiotracer uptake was not only observed in metastases known from conventional CT, but also seen in subcentimeter lymph nodes located in typical metastatic sites of pancreatic cancer, which were not abnormal on routine clinical imaging studies. A significant fraction of the patients demonstrated very high and, over time, increased uptake of MVT-2163 in tumor tissue, suggesting that HuMab-5B1 labeled with beta-emitting radioisotopes may have the potential to deliver therapeutic doses of radiation to cancer cells.

Conclusions: Our study shows that the tumor antigen CA19-9 secreted to the circulation can be used for sensitive detection of primary tumors and metastatic disease by immuno-PET. This significantly broadens the number of molecular targets that can be used for PET imaging and offers new opportunities for noninvasive characterization of tumors in patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052809PMC
December 2019

Driving the Future of Nuclear Medicine.

J Nucl Med 2019 09;60(Suppl 2):1S-2S

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

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http://dx.doi.org/10.2967/jnumed.119.232264DOI Listing
September 2019