Publications by authors named "Matthias Miederer"

49 Publications

Iodine-124 PET quantification of organ-specific delivery and expression of NIS-encoding RNA.

EJNMMI Res 2021 Feb 10;11(1):14. Epub 2021 Feb 10.

TRON - Translational Oncology at the University Medical Center, Johannes Gutenberg University Mainz gGmbH, Mainz, Germany.

Background: RNA-based vaccination strategies tailoring immune response to specific reactions have become an important pillar for a broad range of applications. Recently, the use of lipid-based nanoparticles opened the possibility to deliver RNA to specific sites within the body, overcoming the limitation of rapid degradation in the bloodstream. Here, we have investigated whether small animal PET/MRI can be employed to image the biodistribution of RNA-encoded protein. For this purpose, a reporter RNA coding for the sodium-iodide-symporter (NIS) was in vitro transcribed in cell lines and evaluated for expression. RNA-lipoplex nanoparticles were then assembled by complexing RNA with liposomes at different charge ratios, and functional NIS protein translation was imaged and quantified in vivo and ex vivo by Iodine-124 PET upon intravenous administration in mice.

Results: NIS expression was detected on the membrane of two cell lines as early as 6 h after transfection and gradually decreased over 48 h. In vivo and ex vivo PET/MRI of anionic spleen-targeting or cationic lung-targeting NIS-RNA lipoplexes revealed a visually detectable rapid increase of Iodine-124 uptake in the spleen or lung compared to control-RNA-lipoplexes, respectively, with minimal background in other organs except from thyroid, stomach and salivary gland.

Conclusions: The strong organ selectivity and high target-to-background acquisition of NIS-RNA lipoplexes indicate the feasibility of small animal PET/MRI to quantify organ-specific delivery of RNA.
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http://dx.doi.org/10.1186/s13550-021-00753-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876195PMC
February 2021

Characterization of activation induced [18]F-FDG uptake in Dendritic Cells.

Nuklearmedizin 2021 Apr 16;60(2):90-98. Epub 2020 Dec 16.

Department of Nuclear Medicine, University Medical Center Mainz, Germany.

Aim:  Activation of immune cells leads to enhanced glucose uptake that can be visualized by []F-Fluorodeoxyglucose ([]F-FDG) positron emission tomography/computed tomography (PET/CT). Dendritic cells (DC) are essential for the function of the adaptive immune system. In contrast to other immune cells metabolic changes leading to an increase of []F-FDG uptake are poorly investigated. Here, we analysed the impact of different DC activation pathways on their []F-FDG uptake. This effect was then used to radiolabel DC with []F-FDG and track their migration in vivo.

Methods:  DC were generated from bone marrow progenitors (BMDC) or isolated from spleens (SPDC) of C57BL/6 mice. After stimulation with the TLR ligands LPS and CpG or anti-CD40 antibody for up to 72 hours activation markers and glucose transporters (GLUTs) were measured by flow cytometry. Uptake of []F-FDG was measured by gamma-counting. DC lysates were analysed for expression of glycolysis relevant proteins by mass spectrometry (MS). []F-FDG-labeled DC were injected into footpads of mice to image DC migration.

Results:  BMDC and SPDC showed strong upregulation of activation markers predominantly 24 hours after TLR stimulation followed by higher uptake of []F-FDG. In line with this, the expression of GLUTs was upregulated during the course of activation. Furthermore, MS analyses of DC lysates revealed differential regulation of glycolysis relevant proteins according to the stimulatory pathway. As a proof of principle, DC were labeled with []F-FDG upon activation to follow their migration in vivo via PET/MRI.

Conclusion:  Immune stimulation of DC leads to enhanced []F-FDG uptake into DC, representing the typical shift to aerobic glycolysis in immune cells after activation.
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http://dx.doi.org/10.1055/a-1308-0589DOI Listing
April 2021

Efficacy and Toxicity of Different Chemotherapy Protocols for Concurrent Chemoradiation in Non-Small Cell Lung Cancer-A Secondary Analysis of the PET Plan Trial.

Cancers (Basel) 2020 Nov 13;12(11). Epub 2020 Nov 13.

Department of Radiation Oncology, Medical Center-University of Freiburg, Robert-Koch-Str. 3, 79106 Freiburg, Germany.

(1) Background: The optimal chemotherapy (CHT) regimen for concurrent chemoradiation (cCRT) is not well defined. In this secondary analysis of the international randomized PET-Plan trial, we evaluate the efficacy of different CHT. (2) Methods: Patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume definition and received isotoxically dose-escalated cCRT using cisplatin 80 mg/m (day 1, 22) and vinorelbin 15 mg/m (day 1, 8, 22, 29) (P1) or cisplatin 20 mg/m (day 1-5, 29-33) and vinorelbin 12.5 mg/m (day 1, 8, 15, 29, 36, 43) (P2) or carboplatin AUC1 (day 1-5, 29-33) and vinorelbin 12.5 mg/m (day 1, 8, 15, 29, 36, 43) (P3) or other CHT at the treating physician's discretion. (3) Results: Between 05/2009 and 11/2016, 205 patients were randomized and 172 included in the per-protocol analysis. Patients treated in P1 or P2 had a better overall survival (OS) compared to P3 ( = 0.015, = 0.01, respectively). Patients treated with carboplatin had a worse OS compared to cisplatin (HR 1.78, = 0.03), but the difference did not remain significant after adjusting for age, ECOG, cardiac function creatinine and completeness of CHT. (4) Conclusions: Carboplatin doublets show no significant difference compared to cisplatin, after adjusting for possibly relevant factors, probably due to existing selection bias.
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http://dx.doi.org/10.3390/cancers12113359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697287PMC
November 2020

Dual-Time Point [Ga]Ga-PSMA-11 PET/CT Hybrid Imaging for Staging and Restaging of Prostate Cancer.

Cancers (Basel) 2020 Sep 28;12(10). Epub 2020 Sep 28.

Clinic of Nuclear Medicine, Johannes Gutenberg-University, 55101 Mainz, Germany.

Routine [Ga]Ga-PSMA-11 PET/CT (one hour post-injection) has been shown to accurately detect prostate cancer (PCa) lesions. The goal of this study is to evaluate the benefit of a dual-time point imaging modality for the staging and restaging of PCa patients. Biphasic [Ga]Ga-PSMA-11 PET/CT of 233 patients, who underwent early and late scans (one/three hours post-injection), were retrospectively studied. Tumor uptake and biphasic lesion detection for 215 biochemically recurrent patients previously treated for localized PCa (prostatectomized patients (P-P)/irradiated patients (P-I) and 18 patients suspected of having primary PCa (P-T) were separately evaluated. Late [Ga]Ga-PSMA-11 PET/CT imaging detected 554 PCa lesions in 114 P-P patients, 187 PCa lesions in 33 P-I patients, and 47 PCa lesions in 13 P-T patients. Most patients (106+32 P-P/P-I, 13 P-T) showed no additional PCa lesions. However, 11 PSMA-avid lesions were only detected in delayed images, and 33 lesions were confirmed as malignant by a SUVmax increase. The mean SUVmax of pelvic lymph node metastases was 25% higher ( < 0.001) comparing early and late PET/CT. High positivity rates from routine [Ga]Ga-PSMA-11 PET/CT for the staging and restaging of PCa patients were demonstrated. There was no decisive influence of additional late imaging with PCa lesion detection on therapeutic decisions. However, in a few individual cases, additional delayed scans provided an information advantage in PCa lesion detection due to higher tracer uptake and improved contrast.
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http://dx.doi.org/10.3390/cancers12102788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600341PMC
September 2020

An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma.

Nature 2020 09 29;585(7823):107-112. Epub 2020 Jul 29.

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

Treating patients who have cancer with vaccines that stimulate a targeted immune response is conceptually appealing, but cancer vaccine trials have not been successful in late-stage patients with treatment-refractory tumours. We are testing melanoma FixVac (BNT111)-an intravenously administered liposomal RNA (RNA-LPX) vaccine, which targets four non-mutated, tumour-associated antigens that are prevalent in melanoma-in an ongoing, first-in-human, dose-escalation phase I trial in patients with advanced melanoma (Lipo-MERIT trial, ClinicalTrials.gov identifier NCT02410733). We report here data from an exploratory interim analysis that show that melanoma FixVac, alone or in combination with blockade of the checkpoint inhibitor PD1, mediates durable objective responses in checkpoint-inhibitor (CPI)-experienced patients with unresectable melanoma. Clinical responses are accompanied by the induction of strong CD4 and CD8 T cell immunity against the vaccine antigens. The antigen-specific cytotoxic T-cell responses in some responders reach magnitudes typically reported for adoptive T-cell therapy, and are durable. Our findings indicate that RNA-LPX vaccination is a potent immunotherapy in patients with CPI-experienced melanoma, and suggest the general utility of non-mutant shared tumour antigens as targets for cancer vaccination.
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http://dx.doi.org/10.1038/s41586-020-2537-9DOI Listing
September 2020

Imaging-based target volume reduction in chemoradiotherapy for locally advanced non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomised, controlled trial.

Lancet Oncol 2020 04 12;21(4):581-592. Epub 2020 Mar 12.

Department of Radiation Oncology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; German Cancer Consortium Partner Site Freiburg and German Cancer Research Center, Heidelberg, Germany.

Background: With increasingly precise radiotherapy and advanced medical imaging, the concept of radiotherapy target volume planning might be redefined with the aim of improving outcomes. We aimed to investigate whether target volume reduction is feasible and effective compared with conventional planning in the context of radical chemoradiotherapy for patients with locally advanced non-small-cell lung cancer.

Methods: We did a multicentre, open-label, randomised, controlled trial (PET-Plan; ARO-2009-09) in 24 centres in Austria, Germany, and Switzerland. Previously untreated patients (aged older than 18 years) with inoperable locally advanced non-small-cell lung cancer suitable for chemoradiotherapy and an Eastern Cooperative Oncology Group performance status of less than 3 were included. Undergoing F-fluorodeoxyglucose (F-FDG) PET and CT for treatment planning, patients were randomly assigned (1:1) using a random number generator and block sizes between four and six to target volume delineation informed by F-FDG PET and CT plus elective nodal irradiation (conventional target group) or target volumes informed by PET alone (F-FDG PET-based target group). Randomisation was stratified by centre and Union for International Cancer Control stage. In both groups, dose-escalated radiotherapy (60-74 Gy, 2 Gy per fraction) was planned to the respective target volumes and applied with concurrent platinum-based chemotherapy. The primary endpoint was time to locoregional progression from randomisation with the objective to test non-inferiority of F-FDG PET-based planning with a prespecified hazard ratio (HR) margin of 1·25. The per-protocol set was included in the primary analysis. The safety set included all patients receiving any study-specific treatment. Patients and study staff were not masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT00697333.

Findings: From May 13, 2009, to Dec 5, 2016, 205 of 311 recruited patients were randomly assigned to the conventional target group (n=99) or the F-FDG PET-based target group (n=106; the intention-to-treat set), and 172 patients were treated per protocol (84 patients in the conventional target group and 88 in the F-FDG PET-based target group). At a median follow-up of 29 months (IQR 9-54), the risk of locoregional progression in the F-FDG PET-based target group was non-inferior to, and in fact lower than, that in the conventional target group in the per-protocol set (14% [95% CI 5-21] vs 29% [17-38] at 1 year; HR 0·57 [95% CI 0·30-1·06]). The risk of locoregional progression in the F-FDG PET-based target group was also non-inferior to that in the conventional target group in the intention-to-treat set (17% [95% CI 9-24] vs 30% [20-39] at 1 year; HR 0·64 [95% CI 0·37-1·10]). The most common acute grade 3 or worse toxicity was oesophagitis or dysphagia (16 [16%] of 99 patients in the conventional target group vs 17 [16%] of 105 patients in the F-FDG PET-based target group); the most common late toxicities were lung-related (12 [12%] vs 11 [10%]). 20 deaths potentially related to study treatment were reported (seven vs 13).

Interpretation: F-FDG PET-based planning could potentially improve local control and does not seem to increase toxicity in patients with chemoradiotherapy-treated locally advanced non-small-cell lung cancer. Imaging-based target volume reduction in this setting is, therefore, feasible, and could potentially be considered standard of care. The procedures established might also support imaging-based target volume reduction concepts for other tumours.

Funding: German Cancer Aid (Deutsche Krebshilfe).
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http://dx.doi.org/10.1016/S1470-2045(20)30013-9DOI Listing
April 2020

PSA and PSA Kinetics Thresholds for the Presence of Ga-PSMA-11 PET/CT-Detectable Lesions in Patients With Biochemical Recurrent Prostate Cancer.

Cancers (Basel) 2020 Feb 8;12(2). Epub 2020 Feb 8.

Clinic of Nuclear Medicine, Johannes Gutenberg-University, 55101 Mainz, Germany.

Ga-PSMA-11 positron-emission tomography/computed tomography (PET/CT) is commonly used for restaging recurrent prostate cancer (PC) in European clinical practice. The goal of this study is to determine the optimum time for performing these PET/CT scans in a large cohort of patients by identifying the prostate-specific-antigen (PSA) and PSA kinetics thresholds for detecting and localizing recurrent PC. This retrospective analysis includes 581 patients with biochemical recurrence (BC) by definition. The performance of Ga-PSMA-11 PET/CT in relation to the PSA value at the scan time as well as PSA kinetics was assessed by the receiver-operating-characteristic-curve (ROC) generated by plotting sensitivity versus 1-specificity. Malignant prostatic lesions were identified in 77%. For patients that were treated with radical prostatectomy (RP) a PSA value of 1.24 ng/mL was found to be the optimal cutoff level for predicting positive and negative scans, while for patients previously treated with radiotherapy (RT) it was 5.75 ng/mL. In RP-patients with PSA value <1.24 ng/mL, 52% scans were positive, whereas patients with PSA ≥1.24 ng/mL had positive scan results in 87%. RT-patients with PSA <5.75 ng/mL had positive scans in 86% and and for those with PSA ≥5.75 ng/mL 94% had positive scans. This study identifies the PSA and PSA kinetics threshold levels for the presence of Ga-PSMA-11 PET/CT-detectable PC-lesions in BC patients.
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http://dx.doi.org/10.3390/cancers12020398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072299PMC
February 2020

Evaluation of a novel monoclonal antibody against tumor-associated MUC1 for diagnosis and prognosis of breast cancer.

Int J Med Sci 2019 14;16(9):1188-1198. Epub 2019 Aug 14.

Institute for Immunology, University Medical Center.

There is still a great unmet medical need concerning diagnosis and treatment of breast cancer which could be addressed by utilizing specific molecular targets. Tumor-associated MUC1 is expressed on over 90 % of all breast cancer entities and differs strongly from its physiological form on epithelial cells, therefore presenting a unique target for breast cancer diagnosis and antibody-mediated immune therapy. Utilizing an anti-tumor vaccine based on a synthetically prepared glycopeptide, we generated a monoclonal antibody (mAb) GGSK-1/30, selectively recognizing human tumor-associated MUC1. This antibody targets exclusively tumor-associated MUC1 in the absence of any binding to MUC1 on healthy epithelial cells thus enabling the generation of breast tumor-specific radiolabeled immune therapeutic tools. MAb GGSK-1/30 was used for immunohistochemical analysis of human breast cancer tissue. Its desferrioxamine (Df')-conjugate was synthesized and labelled with Zr. [Zr]Zr-Df'-GGSK-1/30 was evaluated as a potential PET tracer. Binding and pharmacokinetic properties of [Zr]Zr-Df'-GGSK-1/30 were analyzed using human and murine cell lines that express tumor-associated MUC1. Self-generated primary murine breast cancer cells expressing human tumor-associated MUC1 were transplanted subcutaneously in wild type and human MUC1-transgenic mice. The pharmacology of [Zr]Zr-Df'-GGSK-1/30 was investigated using breast tumor-bearing mice by PET/MRT imaging as well as by organ biodistribution analysis. The mAb GGSK-1/30 stained specifically human breast tumor tissue and can be possibly used to predict the severity of disease progression based on the expression of the tumor-associated MUC1. For imaging, the Df'-conjugated mAb was radiolabeled with a radiochemical yield of 60 %, a radiochemical purity of 95 % and an apparent specific activity of 6.1 GBq/µmol. After 7 d, stabilities of 84 % in human serum and of 93 % in saline were observed. cell studies showed strong binding to human tumor-associated MUC1 expressing breast cancer cells. The breast tumor-bearing mice showed an tumor uptake of >50 %ID/g and clearly visible specific enrichment of the radioconjugate PET/MRT. Tumor-associated MUC1 is a very important biomarker for breast cancer next to the traditional markers estrogen receptor (ER), progesterone receptor (PR) and HER/2-neu. The mAb GGSK-1/30 can be used for the diagnosis of over 90% of breast cancers, including triple negative breast cancer based on biopsy staining. Its radioimmunoconjugate represents a promising PET-tracer for breast cancer imaging selectively targeting breast cancer cells.
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http://dx.doi.org/10.7150/ijms.35452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775261PMC
April 2020

Restricting Glycolysis Preserves T Cell Effector Functions and Augments Checkpoint Therapy.

Cell Rep 2019 10;29(1):135-150.e9

Department of Chemistry, The Scripps Research Institute, Scripps-Florida, Jupiter, FL, USA.

Tumor-derived lactic acid inhibits T and natural killer (NK) cell function and, thereby, tumor immunosurveillance. Here, we report that melanoma patients with high expression of glycolysis-related genes show a worse progression free survival upon anti-PD1 treatment. The non-steroidal anti-inflammatory drug (NSAID) diclofenac lowers lactate secretion of tumor cells and improves anti-PD1-induced T cell killing in vitro. Surprisingly, diclofenac, but not other NSAIDs, turns out to be a potent inhibitor of the lactate transporters monocarboxylate transporter 1 and 4 and diminishes lactate efflux. Notably, T cell activation, viability, and effector functions are preserved under diclofenac treatment and in a low glucose environment in vitro. Diclofenac, but not aspirin, delays tumor growth and improves the efficacy of checkpoint therapy in vivo. Moreover, genetic suppression of glycolysis in tumor cells strongly improves checkpoint therapy. These findings support the rationale for targeting glycolysis in patients with high glycolytic tumors together with checkpoint inhibitors in clinical trials.
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http://dx.doi.org/10.1016/j.celrep.2019.08.068DOI Listing
October 2019

Using immuno-PET imaging to monitor kinetics of T cell-mediated inflammation and treatment efficiency in a humanized mouse model for GvHD.

Eur J Nucl Med Mol Imaging 2020 05 31;47(5):1314-1325. Epub 2019 Aug 31.

Department of Nuclear Medicine, University Medical Center Mainz, Langenbeckstr. 1, 55131, Mainz, Germany.

Purpose: Hematopoietic stem cell transplantation is the only curative treatment for several hematological malignancies and immune deficiency syndromes. Nevertheless, the development of graft-versus-host disease (GvHD) after transplantation is a severe complication with high morbidity and mortality. The aim of this study was to image human T cells during GvHD development and their migration into GvHD-related organs. By using a radiolabeled anti-human CD3 monoclonal antibody (mAb), we were able to visualize GvHD progression in a humanized mouse model.

Methods: Human peripheral blood mononuclear cells (PBMC) were transferred into immunodeficient mice (initially n = 11 mice/group) to induce GvHD. One group additionally received regulatory T cells (Treg) for prevention of GvHD. T cell migration was visualized by sequential small animal PET/MRI using Zr-labeled anti-human CD3 mAb. Flow cytometry and immunohistochemistry were used to measure T cell frequencies in relevant organs at different time points after engraftment.

Results: Using radiolabeled anti-CD3 mAb, we successfully visualized human T cells in inflamed organs of mice by Zr-anti-CD3-PET/MRI. Upon GvHD progression, we observed increased numbers of CD3 T cells in the liver (22.9% on day 3; 94.2% on day 10) and the spleen (4.4% on day 3; 58.8% on day 10) which correlated with clinical symptoms. The liver showed distinct spot-like lesions representing a strong focal accumulation of T cells. Administration of Treg prior GvHD induction reduced T cell accumulation in the liver from 857 ± 177 CD3 cells/mm to 261 ± 82 CD3 cells/mm and thus prevented GvHD.

Conclusion: Zr-labeled anti-human CD3 mAb can be used as a proof of concept to detect the exact spatio-temporal distribution of GvHD-mediating T cells. In the future, radiolabeled T cell-specific mAb could be employed as a predictive early biomarker during the course of GvHD maybe even before clinical signs of the disease become evident. Furthermore, monitoring T cell migration and proliferation might improve tailored GvHD therapy.
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http://dx.doi.org/10.1007/s00259-019-04507-0DOI Listing
May 2020

Evaluation of the inverse electron demand Diels-Alder reaction in rats using a scandium-44-labelled tetrazine for pretargeted PET imaging.

EJNMMI Res 2019 May 28;9(1):49. Epub 2019 May 28.

Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.

Background: Pretargeted imaging allows the use of short-lived radionuclides when imaging the accumulation of slow clearing targeting agents such as antibodies. The biotin-(strept)avidin and the bispecific antibody-hapten interactions have been applied in clinical pretargeting studies; unfortunately, these systems led to immunogenic responses in patients. The inverse electron demand Diels-Alder (IEDDA) reaction between a radiolabelled tetrazine (Tz) and a trans-cyclooctene (TCO)-functionalized targeting vector is a promising alternative for clinical pretargeted imaging due to its fast reaction kinetics. This strategy was first applied in nuclear medicine using an In-labelled Tz to image TCO-functionalized antibodies in tumour-bearing mice. Since then, the IEDDA has been used extensively in pretargeted nuclear imaging and radiotherapy; however, these studies have only been performed in mice. Herein, we report the Sc labelling of a Tz and evaluate it in pretargeted imaging in Wistar rats.

Results: Sc was obtained from an in house Ti/Sc generator. A 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-functionalized tetrazine was radiolabelled with Sc resulting in radiochemical yields of 85-95%, a radiochemical purity > 99% at an apparent molar activity of 1 GBq/mmol. The Sc-labelled Tz maintained stability in solution for up to 24 h. A TCO-functionalized bisphosphonate, which accumulates in skeletal tissue, was used as a targeting vector to evaluate the Sc-labelled Tz. Biodistribution data of the Sc-labelled Tz showed specific uptake (0.9 ± 0.3% ID/g) in the bones (humerus and femur) of rats pre-treated with the TCO-functionalized bisphosphonate. This uptake was not present in rats not receiving pre-treatment (< 0.03% ID/g).

Conclusions: We have prepared a Sc-labelled Tz and used it in pretargeted PET imaging with rats treated with TCO-functionalized bisphosponates. This allowed for the evaluation of the IEDDA reaction in animals larger than a typical mouse. Non-target accumulation was low, and there was a 30-fold higher bone uptake in the pre-treated rats compared to the non-treated controls. Given its convenient half-life and the ability to perform positron emission tomography with a previously studied DOTA-functionalized Tz, scandium-44 (t = 3.97 h) proved to be a suitable radioisotope for this study.
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http://dx.doi.org/10.1186/s13550-019-0520-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538705PMC
May 2019

Peptide Receptor Radionuclide Therapy Combined With Chemotherapy in Patients With Neuroendocrine Tumors.

Clin Nucl Med 2019 May;44(5):e329-e335

From the Departments of Nuclear Medicine and.

Purpose: Combinations of therapies may enhance therapeutic effects without significantly increasing the incidence of adverse events. However, there are few data regarding survival after concomitant chemotherapy and peptide receptor radionuclide therapy (PRRT) with [Lu]Lu-octreotate in patients with neuroendocrine tumors (NETs). Thus, we explored the outcome of this combination of therapies.

Methods: Fifteen patients with somatostatin receptor-positive, rapidly progressive G2/G3 NETs during chemotherapy or PRRT alone from 2 German cancer centers were included in the retrospective analysis. The patients received a combination of PRRT and chemotherapy with temozolomide (n = 3) or temozolomide plus capecitabine (n = 12). To evaluate the effects of the combined treatment, we assessed the responses, survival, and adverse events.

Results: The cumulative administered activity of [Lu]Lu-octreotate had a median of 21.3 GBq after 3 cycles of combination therapy. The patients exhibited a median progression-free survival of 7.1 months and a median overall survival of 25.3 months. The clinical benefit (objective response and stable disease) rates were as follows: 55% of patients according to CT, 38% in [F]F-FDG PET/CT, and 44% in [Ga]Ga-DOTATOC PET/CT. One patient with rapidly progressing liver metastases experienced grade 4 liver failure according to the Common Terminology Criteria for Adverse Events (version 5.0). Four other patients (27%) experienced significantly elevated (grade 3) liver parameters.

Conclusions: According to different imaging modalities, the combination of PRRT and temozolomide +/- capecitabine led to disease control in 38% to 55% of the progressive NETs after PRRT or chemotherapy alone failed. The overall survival in this extensively pretreated group of patients was nearly 25 months. The majority of patients did not experience any serious adverse events.
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http://dx.doi.org/10.1097/RLU.0000000000002532DOI Listing
May 2019

Ga[Ga]-, In[In]-oxine: a novel strategy of radiolabeling of HPMA-based micelles.

Am J Nucl Med Mol Imaging 2019 15;9(1):67-83. Epub 2019 Feb 15.

Institute of Nuclear Chemistry, Johannes Gutenberg-University Fritz-Straßmann-Weg 2, Mainz 55128, Germany.

Polymeric micelles are of increasing interest as drug delivery vehicles since they can accumulate in tumor tissue through EPR effect and deliver their hydrophobic cargo. The pharmacology can be visualized and quantified noninvasively by molecular imaging techniques. Here, a novel, fast and efficient technique for radiolabeling various HPMA-LMA based micellar aggregates with hydrophobic oxine-complexes of the trivalent radiometals Ga and In was investigated. The radiometal-oxine complexes resemble the hydrophobic drug In[In]-oxine considered for the diagnosis of infection and inflammation. Promising stability lead to evaluation in healthy mice in terms of quantitative organ distribution. The results show that while the hydrophobic radiometal-oxine complexes were safely encapsulated in aqueous saline, they left the polymeric micelles slowly in contact with blood serum and more rapidly . Due to the similarity between the radiometal complexes and hydrophobic drugs transported in the polymeric micelles this has significant implications for further strategies on transport mechanisms of hydrophobically encapsulated drugs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420711PMC
February 2019

Evaluation of Radiolabeled Girentuximab In Vitro and In Vivo.

Pharmaceuticals (Basel) 2018 Nov 28;11(4). Epub 2018 Nov 28.

Clinic for Nuclear Medicine, University Medical Center Mainz, 55131 Mainz, Germany.

Girentuximab (cG250) targets carbonic anhydrase IX (CAIX), a protein which is expressed on the surface of most renal cancer cells (RCCs). cG250 labeled with Lu has been used in clinical trials for radioimmunotherapy (RIT) of RCCs. In this work, an extensive characterization of the immunoconjugates allowed optimization of the labeling conditions with Lu while maintaining immunoreactivity of cG250, which was then investigated in in vitro and in vivo experiments. cG250 was conjugated with S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (DOTA(SCN)) by using incubation times between 30 and 90 min and characterized by mass spectrometry. Immunoconjugates with five to ten DOTA(SCN) molecules per cG250 molecule were obtained. Conjugates with ratios less than six DOTA(SCN)/cG250 had higher in vitro antigen affinity, both pre- and postlabeling with Lu. Radiochemical stability increased, in the presence of sodium ascorbate, which prevents radiolysis. The immunoreactivity of the radiolabeled cG250 tested by specific binding to SK-RC-52 cells decreased when the DOTA content per conjugate increased. The in vivo tumor uptake was < 10% ID/g and independent of the total amount of protein in the range between 5 and 100 µg cG250 per animal. Low tumor uptake was found to be due to significant necrotic areas and heterogeneous CAIX expression. In addition, low vascularity indicated relatively poor accessibility of the CAIX target.
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http://dx.doi.org/10.3390/ph11040132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316122PMC
November 2018

In vivo imaging of the immune response upon systemic RNA cancer vaccination by FDG-PET.

EJNMMI Res 2018 Aug 15;8(1):80. Epub 2018 Aug 15.

Department of Nuclear Medicine, University Medical Center Mainz of Johannes Gutenberg University Mainz, Mainz, Germany.

Background: [F]Fluoro-2-deoxy-2-D-glucose positron emission tomography (FDG-PET) is commonly used in the clinic for diagnosis of cancer and for follow-up of therapy outcome. Additional to the well-established value in tumor imaging, it bears potential to depict immune processes in modern immunotherapies. T cells enhance their glucose consumption upon activation and are crucial effectors for the success of such novel therapies. In this study, we analyzed the T cell immunity in spleen after antigen-specific stimulation of T cells via highly innovative RNA-based vaccines using FDG-PET/MRI. For this purpose, we employed systemic administration of RNA-lipoplexes encoding the endogenous antigen of Moloney murine leukemia virus (gp70) which have been previously shown to induce potent innate as well as adaptive immune mechanisms for cancer immunotherapy. Feasibility of clinical imaging of increased splenic FDG uptake was demonstrated in a melanoma patient participating in a clinical phase 1 trial of a tetravalent RNA-lipoplex cancer vaccine.

Results: We observed exclusive increase of glucose uptake in spleen compared to other organs thanks to liposome-mediated RNA targeting to this immune-relevant organ. In vivo and ex vivo FDG uptake analysis in the spleen of vaccinated mice correlated well with antigen-specific T cell activation. Moreover, the use of an irrelevant (antigen non-specific) RNA also resulted in enhanced FDG uptake early after vaccination through the activation of several other splenic cell populations. The glucose uptake was also dependent on the dose of RNA administered in line with the activation and frequencies of proliferating antigen-specific T cells as well as the general activation pattern of splenic cell populations.

Conclusions: Our preclinical results show rapid and transient vaccination-induced increase of FDG uptake within the spleen reflecting immune activation preceding T cell proliferation. FDG-PET/CT in patients is also capable to image this immune activation resulting in a new potential application of FDG-PET/CT to image immune processes in new immunological therapies.
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http://dx.doi.org/10.1186/s13550-018-0435-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093825PMC
August 2018

Evaluation of [Ac]Ac-DOTA for α-Therapy of Bone Metastases.

Curr Radiopharm 2018 ;11(3):223-230

Institute of Nuclear Chemistry, Johannes Gutenberg University, Mainz, Germany.

Background: Conjugates of bisphosphonates with macrocyclic chelators possess high potential in bone targeted radionuclide imaging and therapy. DOTAZOL, zoledronic acid conjugated to DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), demonstrated promising results in vivo in small animals as well as in first patient applications using 68Ga for diagnosis via PET and the lowenergy β-emitter 177Lu for therapy of painful bone metastases. In consideration of the fact that targeted α-therapy probably offers various advantages over the use of β--emitters, the 225Ac-labelled derivative [225Ac]Ac-DOTAZOL was synthesized and evaluated in vivo. Here, we report on radiolabelling and biodistribution of [225Ac]Ac-DOTAZOL in healthy Wistar rats.

Methods: DOTAZOL was labelled with 225Ac and injected without further purification into the tail vein with activities of 404 ± 47 kBq per animal. Ex vivo biodistribution studies were performed in healthy Wistar rats at 1 hour, 24 hours, 5 days and 10 days post injection. The accumulation of [225Ac]Ac- DOTAZOL on healthy bone and soft tissue organs was determined in terms of SUV. The results were compared to those of other radiolabelled bisphosphonates such as [68Ga]Ga-DOTAZOL and [177Lu]Lu- DOTAZOL. A group of 7 animals was observed over a period of 3 month after application of 394 kBq ± 10 kBq of [225Ac]Ac-DOTAZOL for signs of toxicity. After 3 months, kidneys were microscopically analysed for signs of chronic kidney damage.

Results: Radiolabelling of DOTAZOL with 225Ac at 98 °C provided radiochemical yields ≥98 % within 30 minutes. [225Ac]Ac-DOTAZOL showed high femur uptake (SUVfemur = 4.99 ± 0.97, 10 d p.i.), which was comparable to that of other Me(III)-DOTAZOL derivatives. Ratios between bone uptake and blood pool activity reached levels of 5, 940, 2181 and 2409 at 1 hour, 24 hours, 5 days and 10 days post injection. During the observation period of the first two month no toxicity was observed clinically. Histopathology of kidneys after 3 month revealed significant tubular damage in most of the animals.

Conclusion: [225Ac]Ac-DOTAZOL repeats the well-known pharmacology of DOTAZOL derivatives in preclinical evaluations. It thus may be considered for translational application together with strategies to reduce renal toxicity.
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http://dx.doi.org/10.2174/1874471011666180604083911DOI Listing
January 2019

Comparison of Linear and Hyperbranched Polyether Lipids for Liposome Shielding by F-Radiolabeling and Positron Emission Tomography.

Biomacromolecules 2018 07 27;19(7):2506-2516. Epub 2018 Apr 27.

Institute of Nuclear Chemistry , Johannes Gutenberg University , Fritz-Strassmann-Weg 2 , D-55128 Mainz , Germany.

Multifunctional and highly biocompatible polyether structures play a key role in shielding liposomes from degradation in the bloodstream, providing also multiple functional groups for further attachment of targeting moieties. In this work hyperbranched polyglycerol ( hbPG) bearing lipids with long alkyl chain anchor are evaluated with respect to steric stabilization of liposomes. The branched polyether lipids possess a hydrophobic bis(hexadecyl)glycerol membrane anchor for the liposomal membrane. hbPG was chosen as a multifunctional alternative to PEG, enabling the eventual linkage of multiple targeting vectors. Different hbPG lipids ( M = 2900 and 5200 g mol) were examined. A linear bis(hexadecyl)glycerol-PEG lipid ( M = 3000 g mol) was investigated as well, comparing hbPG and PEG with respect to shielding properties. Radiolabeling of the polymers was carried out using 1-azido-2-(2-(2-[F]fluoroethoxy)ethoxy)ethane ([F]F-TEG-N) via copper-catalyzed alkyne-azide cycloaddition with excellent radiochemical yields exceeding 95%. Liposomes were prepared by the thin-film hydration method followed by repeated extrusion. Use of a custom automatic extrusion device gave access to reproducible sizes of the liposomes (hydrodynamic radius of 60-94 nm). The in vivo fate of the bis(hexadecyl)glycerol polyethers and their corresponding assembled liposome structures were evaluated via noninvasive small animal positron emission tomography (PET) imaging and biodistribution studies (1 h after injection and 4 h after injection) in mice. Whereas the main uptake of the nonliposomal polyether lipids was observed in the kidneys and in the bladder after 1 h due to rapid renal clearance, in contrast, the corresponding liposomes showed uptake in the blood pool as well as in organs with good blood supply, that is, heart and lung over the whole observation period of 4 h. The in vivo behavior of all three liposomal formulations was comparable, albeit with remarkable differences in splenic uptake. Overall, liposomes shielded by the branched polyglycerol lipids show a favorable biodistribution with greatly prolonged blood circulation times, rendering them promising novel nanovesicles for drug transport and targeting.
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http://dx.doi.org/10.1021/acs.biomac.8b00115DOI Listing
July 2018

The impact of the IGF-1 system of cancer cells on radiation response - An study.

Clin Transl Radiat Oncol 2017 Dec 5;7:1-8. Epub 2017 Oct 5.

Department of Endocrinology and Metabolic Diseases, University Medical Center, Mainz, Germany.

Background: Overexpression of the insulin-like growth factor-1 receptor (IGF-1R) is associated with increased cell proliferation, differentiation, transformation, and tumorigenicity. Additionally, signaling involved in the resistance of cancer cells to radiotherapy originates from IGF-1R. The purpose of this study was to investigate the role of the IGF-1 system in the radiation response and further evaluate its effect on the expression of DNA repair pathway genes.

Methods: To inhibit the IGF-1 system, we stably transfected the Caco-2 cell line to express a kinase-deficient IGF-1R mutant. We then studied the effects of this mutation on cell growth, the response to radiation, and clonogenic survival, as well as using a cell viability assay to examine DNA damage and repair. Finally, we performed immunofluorescence for γ-H2AX to examine double-strand DNA breaks and evaluated the expression of 84 key genes involved in DNA repair with a real-time PCR array.

Results: Mutant IGF-1R cells exhibited significantly blunted cell growth and viability, compared to wild-type cells, as well as reduced clonogenic survival after γ-irradiation. However, mutant IGF-1R cells did not show any significant delays in the repair of radiation-induced DNA double-strand breaks. Furthermore, expression of mutant IGF-1R significantly down-regulated the mRNA levels of BRCA2, a major protein involved in homologous recombination DNA repair.

Conclusion: These results indicate that blocking the IGF-1R-mediated signaling cascade, through the expression of a kinase-deficient IGF-1R mutant, reduces cell growth and sensitizes cancer cells to ionizing radiation. Therefore, the IGF-1R system could be a potential target to enhance radio-sensitivity and the efficacy of cancer treatments.
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http://dx.doi.org/10.1016/j.ctro.2017.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862664PMC
December 2017

Comparison Study of Two Differently Clicked F-Folates-Lipophilicity Plays a Key Role.

Pharmaceuticals (Basel) 2018 Mar 17;11(1). Epub 2018 Mar 17.

Hannover Medical School, Department of Nuclear Medicine, Radiopharmaceutical Chemistry, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

Within the last decade, several folate-based radiopharmaceuticals for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been evaluated; however, there is still a lack of suitable F-folates for clinical PET imaging. Herein, we report the synthesis and evaluation of two novel F-folates employing strain-promoted and copper-catalyzed click chemistry. Furthermore, the influence of both click-methods on lipophilicity and pharmacokinetics of the F-folates was investigated. F-Ala-folate and F-DBCO-folate were both stable in human serum albumin. In vitro studies proved their high affinity to the folate receptor (FR). The lipophilic character of the strain-promoted clicked F-DBCO-folate (logD = 0.6) contributed to a higher non-specific binding in cell internalization studies. In the following in vivo PET imaging studies, FR-positive tumors could not be visualized in a maximum intensity projection images. Compared with F-DBCO-folate, F-Ala-folate (logD = -1.4), synthesized by the copper-catalyzed click reaction, exhibited reduced lipophilicity, and as a result an improved in vivo performance and a clear-cut visualization of FR-positive tumors. In view of high radiochemical yield, radiochemical purity and favorable pharmacokinetics, F-Ala-folate is expected to be a promising candidate for FR-PET imaging.
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http://dx.doi.org/10.3390/ph11010030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874726PMC
March 2018

Labeling of DOTA-conjugated HPMA-based polymers with trivalent metallic radionuclides for molecular imaging.

EJNMMI Res 2018 Feb 27;8(1):16. Epub 2018 Feb 27.

Institute of Nuclear Chemistry, Johannes Gutenberg University Mainz, Mainz, Germany.

Background: In this work, the in vitro and in vivo stabilities and the pharmacology of HPMA-made homopolymers were studied by means of radiometal-labeled derivatives. Aiming to identify the fewer amount and the optimal DOTA-linker structure that provides quantitative labeling yields, diverse DOTA-linker systems were conjugated in different amounts to HPMA homopolymers to coordinate trivalent radiometals Me(III)* = gallium-68, scandium-44, and lutetium-177.

Results: Short linkers and as low as 1.6% DOTA were enough to obtain labeling yields > 90%. Alkoxy linkers generally exhibited lower labeling yields than alkane analogues despite of similar chain length and DOTA incorporation rate. High stability of the radiolabel in all examined solutions was observed for all conjugates. Labeling with scandium-44 allowed for in vivo PET imaging and ex vivo measurements of organ distribution for up to 24 h.

Conclusions: This study confirms the principle applicability of DOTA-HPMA conjugates for labeling with different trivalent metallic radionuclides allowing for diagnosis and therapy.
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http://dx.doi.org/10.1186/s13550-018-0372-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829281PMC
February 2018

Highly Loaded Semipermeable Nanocapsules for Magnetic Resonance Imaging.

Macromol Biosci 2018 04 2;18(4):e1700387. Epub 2018 Feb 2.

Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany.

Magnetic resonance imaging has become an essential tool in medicine for the investigation of physiological processes. The key issues related to contrast agents, i.e., substances that are injected in the body for imaging, are the efficient enhancement of contrast, their low toxicity, and their defined biodistribution. Polyurea nanocapsules containing the gadolinium complex Gadobutrol as a contrast agent in high local concentration and high relaxivity up to 40 s mmol L are described. A high concentration of the contrast agent inside the nanocapsules can be ensured by increasing the crystallinity in the shell of the nanocapsules. Nanocapsules from aliphatic polyurea are found to display higher crystallinity and higher relaxivity at an initial Gadobutrol concentration of 0.1 m than aromatic polyurea nanocapsules. The nanocapsules and the contrast agent are clearly identified in cells. After injection, the nanocarriers containing the contrast agent are mostly found in the liver and in the spleen, which allow for a significant contrast enhancement in magnetic resonance imaging.
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http://dx.doi.org/10.1002/mabi.201700387DOI Listing
April 2018

Diagnostic performance of Gallium-PSMA-11 PET/CT to detect significant prostate cancer and comparison with FEC PET/CT.

Oncotarget 2017 Dec 14;8(67):111073-111083. Epub 2017 Nov 14.

Department of Nuclear Medicine, Johannes Gutenberg-University, Mainz, Germany.

Background: Radiolabeled prostate-specific membrane antigen (PSMA) has proven to be a highly accurate method to detect recurrence and metastases of prostate cancer, but only sparse data is available about its performance in the diagnosis of clinically significant primary prostate cancer.

Methods: We compared Ga-PSMA-11 PET/CT in 25 patients with FEC PET/CT in 40 patients with suspected prostate carcinoma based on an increased PSA level.The PET/CT results were compared with the histopathologic Gleason Score (GS) of biopsies.

Results: The Ga-PSMA-11 PET/CT revealed highly suspect prostatic lesions (maximum standardized uptake value/SUV >2.5) in 21/25 patients (84%), associated with GS≥6 (low-grade/high-grade carcinoma). Two histopathologic non-malignancy-relevant cases (GS<6) had PSMA-SUV ≤2.5; all histopathologic high-grade cases (GS≥7b) showed PSMA-SUV >12.0 which further increased with rising GS. There were 2 false positives and no false negative findings for high-grade prostate cancer using a cut off-level for SUV of 2.5.In contrast, the FEC PET/CT showed suspected malignant lesions in 38/40 patients (95%), which included 3 lesions with GS<6. The mean SUV values did not differ with different GS. There were 11 false positives and 1 false negative for detection of high-grade prostate cancer (cut off 2.5).By means of ROC analysis a SUV of 5.4 was found to be an optimal cut off-level to distinguish between low- and high-grade carcinoma in Ga-PSMA-11 PET/CT (AUC=0.9692; 95% CI 0.9086;1.0000;SD(AUC)=0.0309)). Choosing a cut off-level of SUV5.4, Ga-PSMA-11 PET/CT was able to distinguish between GS ≤7a/≥7b with a sensitivity of 84%, a specificity of 100%, a negative predictive value (NPV) of 67%, and an efficiency of 88% (<0.001).The ROC analysis revealed a SUV 6.5 as an optimal cut off-level to distinguish between low- and high-grade carcinoma in FEC PET/CT (AUC=0.7470; 95% CI 0.5919;0.9020;SD(AUC)=0.0791) with a sensitivity of 61% and a specificity of 92%; but the efficiency was only 70% and the NPV 50% (=0.01).

Conclusion: Ga-PSMA-11 PET/CT guided biopsy of the prostate increases diagnostic precision and is likely to help to reduce overtreatment of low-grade malignant disease as well as detect the foci of the highest Gleason pattern. Both methods (Ga-PSMA-11,FEC) were suitable to detect primary prostate cancer, but the excellent image quality, the higher specificity and the good correlation of positive scans with GS are advantages of Ga-PSMA-11.
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http://dx.doi.org/10.18632/oncotarget.22441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762306PMC
December 2017

Inclusion of PET-CT into planning of primary or neoadjuvant chemoradiotherapy of esophageal cancer improves prognosis.

Strahlenther Onkol 2017 Oct 2;193(10):791-799. Epub 2017 Aug 2.

Department of Radiation Oncology and Radiotherapy, University Medical Center, Langenbeckstrasse 1, 55131, Mainz, Germany.

Background: PET-CT is widely used for both the staging and planning of primary or neoadjuvant chemoradiotherapy for esophageal cancer. Inclusion of PET-CT information into radiotherapy planning often leads to substantial modifications of the target volume. In the case of detection of distant metastases, it may also result in a switch to a palliative treatment approach. This spares patients from therapy-related toxicities that provide no clinical benefit. However, due to a lack of studies, it is currently unclear whether the advantages of PET-CT also translate into a measurable improvement in patient survival.

Patients And Methods: A retrospective analysis assessed the survival data of 145 patients with esophageal carcinoma stages I (eight patients; 5%), II (45; 31%), III (79; 55%), IV (8; 5%) and unknown (5; 4%). Patients were treated between 1999 and 2014 either with primary chemoradiation (n = 101) or neoadjuvant chemoradiation at the Department of Radiation Oncology, University Medical Center Mainz, followed by transabdominal or transthoracic tumor resection (n = 44). Of the 145 patients, 64 (44%) had undergone PET-CT.

Results: Univariate analysis showed the use of PET-CT to be associated with significantly longer local recurrence-free survival (p = 0.006) and tended to translate into a measurable improvement of overall survival (p = 0.071). Since more patients underwent surgery in the group planned using PET-CT (20% vs. 44%; p = 0.002), we carried out a multivariate Cox regression analysis to adjust for this possible confounding factor. Surgery (p = 0.042; HR 0.55; 95% confidence interval: 0.31-0.98) as well as the use of PET-CT (p = 0.048; HR 0.60; 95% confidence interval: 0.36-0.99) nearly halved the risk of local recurrence. It was only in the group of patients with PET-CT that a trend towards a shorter overall survival was evident in lymph node-positive patients (p = 0.16), whereas nodal stage did not impact on survival in patients staged without PET-CT (p = 0.97).

Conclusion: To the best of our knowledge these data suggest for the first time that the use of PET-CT in the framework of staging and planning of primary or neoadjuvant chemoradiotherapy for esophageal cancer has a favorable impact on patient survival.
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http://dx.doi.org/10.1007/s00066-017-1164-3DOI Listing
October 2017

[Diagnostic significance of multiparametric MRI combined with US-fusion guided biopsy of the prostate in patients with increased PSA levels and negative standard biopsy results to detect significant prostate cancer - Correlation with the Gleason score. Korrelation mit dem Gleason Score].

Nuklearmedizin 2017 08 17;56(4):147-155. Epub 2017 Jul 17.

Department of Nuclear Medicine, University Medical Center Mainz, Mainz, Germany

Aims: To increase diagnostic precision and to reduce overtreatment of low-risk malignant disease, multiparametric MRI (mpMRI) combined with ultrasound (US) fusion guided biopsy of the prostate were performed.

Methods: In 99 male patients with increased PSA plasma levels and previous negative standard biopsy procedures, mpMRI was carried out followed by US fusion guided perineal biopsy. PI-RADS-Data (PS) of mpMRI and histopathological Gleason score (GS) were categorized and statistically compared.

Results: Lesions in 72/99 (73 %) of patients were determined to be suspect of malignancy, based on a PS 4 or 5. In 33/99 (33 %) of patients, malignancy could not be confirmed by histopathology. With regard to the remaining 66 patients with previous negative biopsy results, 42 (64 %) were diagnosed with a low-grade carcinoma (GS 6, 7a) and 24 (36 %) with a high-grade carcinoma (GS ≥ 7b). The proportion of corresponding results in mpMRI (PS 4-5) when a high-grade carcinoma had been detected, was 21/24 (88 %), which related to a sensitivity of 88 % and a negative predictive value (NPV) of 85 % (p = 0,002). In addition, 35 of 42 patients (83%), graded PS 4-5 in mpMRI, were diagnosed with low-grade carcinoma-positive (p < 0,001). Sensitivity to differentiation between low- and high-grade carcinomas (GS ≤ 7a vs. ≥ 7b) by means of PS was 88 % with a NPV of 70 % (p = 0,74).

Conclusion: Our results suggest that mpMRI combined with US-fusion guided biopsy is able to detect considerably higher rates of clinically relevant prostate malignancies compared to conventional diagnostic procedures. However, no statistical significance could be shown regarding the differentiation between high- and low-grade carcinomas. It is hoped that the hybrid methods PSMA-PET/CT or PSMA-PET/MRI will lead to the next optimization step in the differentiation between high- and low-grade carcinomas which so far has been unsatisfactory.
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http://dx.doi.org/10.3413/Nukmed-0871-16-12DOI Listing
August 2017

Impact of combined FDG-PET/CT and MRI on the detection of local recurrence and nodal metastases in thyroid cancer.

Cancer Imaging 2016 Nov 3;16(1):37. Epub 2016 Nov 3.

Department of Nuclear Medicine, Johannes Gutenberg-University Medical Center, Langenbeckstr. 1, D-55131, Mainz, Germany.

Background: Suspected recurrence of thyroid carcinoma is a diagnostic challenge when findings of both a radio iodine whole body scan and ultrasound are negative. PET/CT and MRI have shown to be feasible for detection of recurrent disease. However, the added value of a consensus reading by the radiologist and the nuclear medicine physician, which has been deemed to be helpful in clinical routines, has not been investigated. This study aimed to investigate the impact of combined FDG-PET/ldCT and MRI on detection of locally recurrent TC and nodal metastases in high-risk patients with special focus on the value of the multidisciplinary consensus reading.

Materials And Methods: Forty-six patients with suspected locally recurrent thyroid cancer or nodal metastases after thyroidectomy and radio-iodine therapy were retrospectively selected for analysis. Inclusion criteria comprised elevated thyroglobulin blood levels, a negative ultrasound, negative iodine whole body scan, as well as combined FDG-PET/ldCT and MRI examinations. Neck compartments in FDG-PET/ldCT and MRI examinations were independently analyzed by two blinded observers for local recurrence and nodal metastases of thyroid cancer. Consecutively, the scans were read in consensus. To explore a possible synergistic effect, FDG-PET/ldCT and MRI results were combined. Histopathology or long-term follow-up served as a gold standard. For method comparison, sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were calculated.

Results: FDG-PET/ldCT was substantially more sensitive and more specific than MRI in detection of both local recurrence and nodal metastases. Inter-observer agreement was substantial both for local recurrence (κ = 0.71) and nodal metastasis (κ = 0.63) detection in FDG-PET/ldCT. For MRI, inter-observer agreement was substantial for local recurrence (κ = 0.69) and moderate for nodal metastasis (κ = 0.55) detection. In contrast, FDG-PET/ldCT and MRI showed only slight agreement (κ = 0.21). However, both imaging modalities identified different true positive results. Thus, the combination created a synergistic effect. The multidisciplinary consensus reading further increased sensitivity, specificity, and diagnostic accuracy.

Conclusions: FDG-PET/ldCT and MRI are complementary imaging modalities and should be combined to improve detection of local recurrence and nodal metastases of thyroid cancer in high-risk patients. The multidisciplinary consensus reading is a key element in the diagnostic approach.
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http://dx.doi.org/10.1186/s40644-016-0096-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093960PMC
November 2016

A DOTA based bisphosphonate with an albumin binding moiety for delayed body clearance for bone targeting.

Nucl Med Biol 2016 Nov 1;43(11):670-678. Epub 2016 Aug 1.

Institute of Nuclear Chemistry, Johannes-Gutenberg-University Mainz, Germany.

Radiolabeled bisphosphonates are commonly used in the diagnosis and therapy of bone metastases. Blood clearance of bisphosphonates is usually fast and only 30%-50% of the injected activity is retained in the skeleton, while most of the activity is excreted by the urinary tract. A longer blood circulation may enhance accumulation of bisphosphonate compounds in bone metastases. Therefore, a chemically modified macrocyclic bisphosphonate derivative with an additional human albumin binding entity was synthesized and pharmacokinetics of its complex was evaluated. The DOTA-bisphosphonate conjugate BPAMD was compared against the novel DOTAGA-derived albumin-binding bisphosphonate DOTAGA(428-d-Lys)M (L1). The ligands were labeled with Ga(III) and were evaluated in in vitro binding studies to hydroxyapatite (HA) as well as to human serum albumin. The compounds were finally compared in in vivo PET and ex vivo organ distribution studies in small animals over 6h. Binding studies revealed a consistent affinity of both bisphosphonate tracers to HA. Small animal PET and ex vivo organ distribution studies showed longer blood retention of [Ga]L1. [Ga]BPAMD is initially more efficiently bound to the bone but skeletal accumulation of the modified compound and [Ga]BPAMD equalized at 6h p.i. Ratios of femur epiphyseal plate to ordinary bone showed to be more favorable for [Ga]L1 than for [Ga]BPAMD due to the longer circulation time of the new tracer. Thus, the chemical modification of BPAMD toward an albumin-binding bisphosphonate, L1, resulted in a novel PET tracer which conserves advantages of both functional groups within one and the same molecule. The properties of this new diagnostic tracer are expected to be preserved in Lu therapeutic agent with the same ligand (a theranostic pair).
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http://dx.doi.org/10.1016/j.nucmedbio.2016.07.009DOI Listing
November 2016

Toll like receptor mediated immune stimulation can be visualized in vivo by [F]FDG-PET.

Nucl Med Biol 2016 Nov 14;43(11):651-660. Epub 2016 Jul 14.

Department of Nuclear Medicine, University Medical Center Mainz, Germany.

Introduction: High uptake of [F]-2-fluorodeoxyglucose ([F]FDG) by inflammatory cells is a frequent cause of false positive results in [F]FDG-positron-emission tomography (PET) for cancer diagnostics. Similar to cancer cells, immune cells undergo significant increases in glucose utilization following activation, e.g., in infectious diseases or after vaccination during cancer therapy. The aim of this study was to quantify certain immune effects in vitro and in vivo by [F]FDG-PET after stimulation with TLR ligands and specific antibodies.

Methods: In vivo [F]FDG-PET/magnetic resonance imaging (MRI) and biodistribution was performed with C57BL/6 mice immunized with CpG or LPS. Cellular [F]FDG-uptake assays were performed with B cells and T cells or with whole spleen cells after stimulation with CpG, LPS and anti-CD3/CD28. In vitro and in vivo activation of B and T cells was examined by concomitant FACS analysis to correlate immune cell activation with the strength of [F]FDG accumulation.

Results: We could show that TLR mediated activation of B cells increases [F]FDG uptake, and that B cells show faster kinetics and greater effect than T cells stimulated by the CD3/CD28 pathway. In the whole spleen cell population the [F]FDG signal was triggered mainly by the activation of B cells, corresponding closely to expression of typical stimulation markers. This finding could also been seen in vivo in [F]FDG-PET/MRI, where the spleen was clearly visible after TLR stimulation and B cells showed upregulation of CD80 and CD86.

Conclusion: In vivo TLR stimulation can be visualized by increased [F]FDG uptake in lymphoid organs. The signal generated in the spleen after immunization might be mainly attributed to the activation of B cells within.

Advances In Knowledge And Implications For Patient Care: Knowledge of the composition of cells that take up [F]FDG during vaccination or in response to therapy may improve successful treatment of cancer patients in the future.
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http://dx.doi.org/10.1016/j.nucmedbio.2016.07.004DOI Listing
November 2016

Harnessing the potential of noninvasive in vivo preclinical imaging of the immune system: challenges and prospects.

Nanomedicine (Lond) 2016 Oct 15;11(20):2711-2722. Epub 2016 Sep 15.

Department of Nuclear Medicine, University Medical Center Mainz, Mainz, Germany.

Preclinical imaging has become a powerful method for investigation of in vivo processes such as pharmacokinetics of therapeutic substances and visualization of physiologic and pathophysiological mechanisms. These are important aspects to understand diseases and develop strategies to modify their progression with pharmacologic interventions. One promising intervention is the application of specifically tailored nanoscale particles that modulate the immune system to generate a tumor targeting immune response. In this complex interaction between immunomodulatory therapies, the immune system and malignant disease, imaging methods are expected to play a key role on the way to generate new therapeutic strategies. Here, we summarize examples which demonstrate the current potential of imaging methods and develop a perspective on the future value of preclinical imaging of the immune system.
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http://dx.doi.org/10.2217/nnm-2016-0187DOI Listing
October 2016

68Ga-DOTATATE PET/CT Interobserver Agreement for Neuroendocrine Tumor Assessment: Results of a Prospective Study on 50 Patients.

J Nucl Med 2017 02 18;58(2):307-311. Epub 2016 Aug 18.

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California

We evaluated observer agreement for Ga-DOTATATE PET/CT interpretations in patients with neuroendocrine tumor (NET).

Methods: Ga-DOTATATE PET/CT was performed on 50 patients with known or suspected NET of the small bowel (n = 19), pancreas (n = 14), lung (n = 4), or other location (n = 13). The images were reviewed by 7 observers, who used a standardized interpretation approach. The observers were classified as having a low level of experience (<500 scans or <5 y experience with Ga-DOTATATE PET/CT; n = 4) or a high level of experience (≥500 scans or ≥5 y experience with Ga-DOTATATE PET/CT; n = 3). Interpretation by the primary nuclear medicine physician, who had access to all clinical and imaging data, served as the reference standard. Interobserver agreement was determined by the Cohen κ statistic and intraclass correlation coefficient (ICC) with corresponding 95% confidence interval (95%CI).

Results: Interobserver agreement was substantial, and the median number of false findings was low for the overall scan result: that is, positive versus negative scan result (κ = 0.80; 95%CI, 0.74-0.86; false findings, 3), organ involvement (κ = 0.70; 95%CI, 0.64-0.76; false findings, 5), and lymph node involvement (κ = 0.71; 95%CI, 0.65-0.78; false findings, 6). Interobserver agreement was substantial to almost perfect, and the average absolute difference (Δ) from the reference observer was low for number of organ and lymph node metastases (organ: ICC, 0.84; 95%CI, 0.77-0.89; Δ = 0.45; lymph node: ICC, 0.77; 95%CI, 0.69-0.84; Δ = 0.45), tumor SUV (ICC, 0.99; 95%CI, 0.97-0.99; Δ = 0.44), and reference SUV (spleen: ICC, 0.81; Δ = 1.10; liver: ICC, 0.79; Δ = 0.62). Interpretations of appropriateness for peptide-receptor radionuclide therapy varied more significantly among observers (κ = 0.64; 95%CI, 0.57-0.70), and a higher frequency of false-positive recommendations for peptide-receptor radionuclide therapy occurred in observers with low experience than in those with high experience (range, 7-12 vs. 4-8).

Conclusion: The interpretation of Ga-DOTATATE PET/CT images for NET staging is consistent among observers with low and high levels of experience. However, image-based recommendations for or against peptide-receptor radionuclide therapy require experience and training.
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http://dx.doi.org/10.2967/jnumed.116.179192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290122PMC
February 2017

Effectiveness and side-effects of peptide receptor radionuclide therapy for neuroendocrine neoplasms in Germany: A multi-institutional registry study with prospective follow-up.

Eur J Cancer 2016 May 2;58:41-51. Epub 2016 Mar 2.

Clinic of Molecular Radiotherapy, Center for Neuroendocrine Tumors Bad Berka - ENETS Center of Excellence, Zentralklinik Bad Berka GmbH, Bad Berka, Germany.

Background: Monocentric and retrospective studies indicate effectiveness of peptide receptor radionuclide therapy targeting somatostatin receptors of neuroendocrine neoplasms. We assessed overall and progression-free survival and adverse events of peptide receptor radionuclide therapy by a multi-institutional, board certified registry with prospective follow-up in five centres in Germany.

Methods: A total of 450 patients were included and followed for a mean of 24.4 months. Most patients had progressive low- or intermediate grade neuroendocrine neoplasms and 73% were pretreated with at least one therapy. Primary neuroendocrine neoplasms were mainly derived of pancreas (38%), small bowel (30%), unknown primary (19%) or bronchial system (4%). Patients were treated with Lutetium-177 in 54%, with Yttrium-90 in 17% and with both radionuclides in 29%. Overall and progression-free survival was determined with Kaplan-Meier curves and uni-variate log rank test Cox models.

Findings: Median overall survival of all patients was 59 (95% confidence interval [CI] 49-68.9) months. Overall survival was significantly inferior in the patients treated with Yttrium-90 solely (hazard ratio, 3.22; 95% CI, 1.83-5.64) compared to any peptide receptor radionuclide therapy with Lutetium-177. Grade II (hazard ratio, 2.06; 95% CI, 0.79-5.32) and grade III (hazard ratio, 4.22; 95% CI, 1.41-12.06) neuroendocrine neoplasms had significantly worse overall survival than grade I neuroendocrine neoplasms. Patients with small neuroendocrine neoplasms of small bowel had significantly increased survival (hazard ratio, 0.39; 95% CI, 0.18-0.87) compared to neuroendocrine neoplasms of other locations. Median progression-free survival was 41 (35.9-46.1) months and significantly inferior in patients treated with Yttrium solely (hazard ratio, 2.7; 95% CI, 1.71-4.55). Complete remission was observed in 5.6% of patients, 22.4% had a partial remission, 47.3% were stable and 4% were progressive as best response. Adverse events of bone marrow and kidney function higher than grade III occurred in 0.2-1.5% of patients.

Interpretation: These results indicate that peptide receptor radionuclide therapy is a highly effective therapy for patients with low to intermediate grade neuroendocrine neoplasms with minor adverse events.
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http://dx.doi.org/10.1016/j.ejca.2016.01.009DOI Listing
May 2016