PSA and PSA Kinetics Thresholds for the Presence of 68Ga-PSMA-11 PET/CT-Detectable Lesions in Patients with Biochemical Recurrent Prostate Cancer

68Ga-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 68Ga-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 plottin…

In vivo Evaluation of [225Ac]Ac-DOTAZOL for α-Therapy of Bone Metastases

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 biodist…

Fate of Linear and Branched Polyether-Lipids In Vivo in Comparison to Their Liposomal Formulations by 18F-Radiolabeling and Positron Emission Tomography

In this study, linear poly(ethylene glycol) (PEG) and novel linear-hyperbranched, amphiphilic polyglycerol (hbPG) polymers with cholesterol (Ch) as a lipid anchor moiety were radiolabeled with fluorine-18 via copper-catalyzed click chemistry. In vivo investigations via positron emission tomography (PET) and ex vivo biodistribution in mice were conducted. A systematic comparison to the liposomal formulations with and without the polymers with respect to their initial pharmacokinetic properties during the first hour was carried out, revealing remarkable differences. Additionally, cholesterol was directly labeled with fluorine-18 and examined likewise. Both polymers, Ch-PEG27-CH2-triazole-TEG-…

Comparison Study of Two Differently Clicked 18F-Folates—Lipophilicity Plays a Key Role

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 18F-folates for clinical PET imaging. Herein, we report the synthesis and evaluation of two novel 18F-folates employing strain-promoted and copper-catalyzed click chemistry. Furthermore, the influence of both click-methods on lipophilicity and pharmacokinetics of the 18F-folates was investigated. 18F-Ala-folate and 18F-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 …

Imaging of T cell-mediated inflammation in a preclinical GvHD model using radiolabeled anti-human CD3 antibody

Highly Loaded Semipermeable Nanocapsules for Magnetic Resonance Imaging.

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-1 mmol-1 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 hi…

Alpha emitting nuclides in nuclear medicine theranostics.

Theranostic applications with radio-isotopes currently are rapidly progressing and expand nuclear medicine application in clinical routine. Alpha emitting isotopes, in particular, have long been hypothesized to achieve relevant advances for the treatment of malignancies. Here, an overview of their properties and the knowledge of radiobiology is reviewed in view of clinical translation. Clinical evidence of radiopharmaceuticals based on alpha emitters is summarized with a focus on recent developments for treatment of metastasized castration resistant prostate cancer.Theranostische Anwendungen mit Radioisotopen machen derzeit rasche Fortschritte und erweitern den Einsatz der Nuklearmedizin in…

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

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 sta…

Targeting of immune cells with trimannosylated liposomes

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

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 health…

Toll like receptor mediated immune stimulation can be visualized in vivo by [ 18 F]FDG-PET

Abstract Introduction High uptake of [ 18 F]-2-fluorodeoxyglucose ([ 18 F]FDG) by inflammatory cells is a frequent cause of false positive results in [ 18 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 [ 18 F]FDG-PET after stimulation with TLR ligands and specific antibodies. Methods In vivo [ 18 F]FDG-PET/magnetic resonance imaging (MRI) and biodistribution was performed with C57BL/6 mice immunized with Cp…

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

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.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 (…

The Impact of Radiotherapy Protocol Adherence on the Treatment Outcome in Patients With Locally Advanced NSCLC Treated With Concurrent Chemoradiation: Results From the Radiotherapy Quality Assurance of the International Randomized PET-Plan Trial

PURPOSE/OBJECTIVE(S) The success of intensification and personalization of the curative treatment of non-small cell lung cancer (NSCLC) is strongly associated with the precision in radiotherapy (RT) treatment, which must therefore follow high standards. Herein we evaluate the impact of RT protocol adherence in the prospective international multicenter trial on curative treatment of NSCLC. MATERIALS/METHODS In the open-label, randomized, controlled PET-Plan trial, patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume delineation informed by ¹⁸F-FDG PET and CT plus elective nodal irradiation (Arm A) or target volumes informed by PET alone (Arm B) and receiv…

Peptide receptor radionuclide therapy combined with chemotherapy

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

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)…

A shared tumor-antigen RNA-lipoplex vaccine with/without anti-PD1 in patients with checkpoint-inhibition experienced melanoma.

3136 Background: Cancer vaccines are considered unsuitable for patients with advanced tumours and have not been clinically successful. Methods: Lipo-MERIT is an ongoing phase 1/2 trial (NCT02410733) with melanoma FixVac, a liposomal RNA vaccine targeting four non-mutant shared tumour-associated antigens (TAAs) (MAGE-A3, NY-ESO-1, tyrosinase, TPTE). Patients with stage IIIB-C and IV melanoma are eligible. The trial comprises 7 dose escalation and 3 dose expansion cohorts, the latter with FixVac alone or combined with anti-PD1. Eight doses of FixVac are administered i.v. weekly/bi-weekly followed by optional continued monthly treatment. This abstract summarizes the findings of an exploratory…

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

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 111In-labelled Tz to image TC…

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

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 thera…

Molecular imaging of gastroenteropancreatic neuroendocrine tumors.

Somatostatin-receptor scintigraphy has become an obligatory molecular imaging method in the management of patients with neuroendocrine tumors when metastatic disease is suspected. Using positron emission tomography and new somatostatin analogues, sensitivity of somatostatin receptor imaging has further increased. With a combination of morphologic imaging methods, such as hybrid imaging by PET/CT, this method represents the method of choice in many centers and efforts are under way to translate somatostatin receptor imaging onto a cellular level by endoscopic confocal microscopy. Other clinically relevant functional pathways in neuroendocrine tumors that are accessible by PET imaging are glu…

549 An RNA-lipoplex (RNA-LPX) vaccine demonstrates strong immunogenicity and promising clinical activity in a Phase I trial in cutaneous melanoma patients with no evidence of disease at trial inclusion

BackgroundLipo-MERIT is an ongoing, first-in-human, open-label, dose-escalation Phase I trial investigating safety, tolerability and immunogenicity of BNT111 in patients with advanced melanoma. BNT111 is an RNA-LPX vaccine targeting the melanoma tumor-associated antigens (TAAs) New York esophageal squamous cell carcinoma 1 (NY-ESO-1), tyrosinase, melanoma-associated antigen 3 (MAGE-A3), and transmembrane phosphatase with tensin homology (TPTE). A previous exploratory interim analysis showed that BNT111, alone or combined with immune checkpoint inhibition (CPI), has a favorable adverse event (AE) profile, gives rise to antigen-specific T-cell responses and induces durable objective responses…

Peptide Receptor Radionuclide Therapy for Neuroendocrine Neoplasms in Germany: a Multi-Institutional Registry Study with Prospective Follow Up on 450 Patients

68 Ga-DOTATOC PET in patients with neuroendocrine tumors (NET). We specifically looked for incremental lesions, defined as lesions only observed on one modality even after extensive retrospective evaluation of the other modality. Methods: Twenty patients with a metastasized NET underwent 111 In-pentetreotide

Using mRNA and small RNA gene expression changes in peripheral blood for easy detection of Ra-223 incorporation

Dual-Time Point [68Ga]Ga-PSMA-11 PET/CT Hybrid Imaging for Staging and Restaging of Prostate Cancer

Routine [68Ga]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 [68Ga]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 [68Ga]Ga-PSMA-11 PET/CT …

PET Lung Ventilation/Perfusion Imaging Using 68Ga Aerosol (Galligas) and 68Ga-Labeled Macroaggregated Albumin

Pulmonary imaging using ventilation/perfusion (V/P) single-photon emission tomography (V/P scan) with Tc-99m-labeled radiotracers is a well-established diagnostic tool for clinically suspected pulmonary embolism (PE). Ga-68 aerosol (Galligas) and Ga-68-labeled macroaggregated albumin (MAA) are potential tracers for positron emission tomography (PET) lung V/P imaging and could display an advantage over conventional V/P scans in terms of sensitivity and specificity. After radiochemical and animal studies, the clinical applicability of Ga-68 aerosol (Galligas) and Ga-68-labeled MAA was investigated in an exploratory study in patients with clinical suspicion of PE. PET scans were acquired using…

OA12.05 Imaging-Guided Target Volume Reduction in Radiotherapy of Lung Cancer: The Prospective Randomized Multinational PET-Plan Trial

Additional file 1: of Evaluation of the inverse electron demand Diels-Alder reaction in rats using a scandium-44-labelled tetrazine for pretargeted PET imaging

Figure S1. HPLC radiochromatogram chromatogram of [44Sc]3 (Rt = 5.7 min). Figure S2. In vitro stability of [44Sc]3. (A) radio-TLC analysis of [44Sc]3 with 2 (lane 2) and without 2 (lane 1) following radiosynthesis. (B) Percent intact over time after incubation in saline (red circles) and human serum albumin (blue squares) for 0.5–24 h at 37 °C. Table S1. Summary of the uptake for [44Sc]3 in Wistar rats. Table S2. Summary of bone uptake values (4 h p.i.) and TCO:Tz ratios in individual rats. (DOC 275 kb)

Diagnostic efficacy of Gallium-68-PSMA PET/CT in 565 patients with biochemical recurrence of prostate cancer

Comparison of linear and hyperbranched polyether lipids for liposome shielding by 18F-radiolabeling and positron emission tomography

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 (Mn = 2900 and 5200 g mol-1) were examined. A linear bis(h…

Improved inter-observer agreement of an expert review panel in an oncology treatment trial--Insights from a structured interventional process.

Abstract Purpose Oncologic imaging is a key for successful cancer treatment. While the quality assurance (QA) of image acquisition protocols has already been focussed, QA of reading and reporting offers still room for improvement. The latter was addressed in the context of a prospective multicentre trial on fluoro-deoxyglucose (FDG)–positron-emission tomography (PET)/CT-based chemoradiotherapy for locally advanced non-small cell lung cancer (NSCLC). Material and methods An expert panel was prospectively installed performing blinded reviews of mediastinal NSCLC involvement in FDG–PET/CT. Due to a high initial reporting inter-observer disagreement, the independent data monitoring committee (I…