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Abstract Background Radiohybrid PSMA-targeted ligands (rhPSMA) have been introduced as a novel platform for theranostic applications. Among a variety of rhPSMA-ligands developed for radioligand therapy, two stereoisomers [177Lu]Lu-rhPSMA-10.1 and -10.2 have been synthesized and initially characterized in preclinical experiments with the aim to provide an optimized binding profile to human serum albumin, a reduction of charge, and thus accelerated kidney excretion, and unaffected or even improved tumor uptake. As both isomers showed similar in vitro characteristics and tumor uptake at 24 h post injection in tumor bearing mice and in order to identify the isomer with the most favorable pharmacokinetics for radioligand therapy, we carried out in-depth biodistribution and dosimetry studies in tumor-bearing and healthy mice. Results rhPSMA-10.1 and -10.2 were radiolabeled with lutetium-177 according to the established procedures of other DOTA-based PSMA ligands and displayed a high and comparable stability in all buffers and human serum (> 97%, 24 h). Biodistribution studies revealed fast clearance from the blood pool (0.3–0.6%ID/g at 1 h) and other background tissues within 48 h. Distinctive differences were found in the kidneys, where [177Lu]Lu-rhPSMA-10.1 displayed lower initial uptake and faster excretion kinetics compared to [177Lu]Lu-rhPSMA-10.2 expressed by a 1.5-fold and ninefold lower uptake value at 1 h and 24 h in healthy animals, respectively. Tumor uptake was comparable and in the range of 8.6–11.6%ID/g for both isomers over 24 h and was maintained up to 168 h at a level of 2.2 ± 0.8 and 4.1 ± 1.4%ID/g for [177Lu]Lu-rhPSMA-10.1 and [177Lu]Lu-rhPSMA-10.2, respectively. Conclusion Our preclinical data on biodistribution and dosimetry indicate a more favorable profile of [177Lu]Lu-rhPSMA-10.1 compared to [177Lu]Lu-rhPSMA-10.2 for PSMA-targeted radioligand therapy. [177Lu]Lu-rhPSMA-10.1 shows fast kidney clearance kinetics resulting in excellent tumor-to-organ ratios over a therapy relevant time course. Meanwhile, [177Lu]Lu-rhPSMA-10.1 is currently being investigated in clinical phase I/II studies in patients with mCRPC (NCT05413850), in patients with high-risk localized PC (NCT06066437, Nautilus Trial) and after external beam radiotherapy (NCT06105918).

This work investigates composites from renewable resources that exhibit high flexibility. The effect of three different weft-knitted structures on the tensile properties, flexural properties, tear resistance and puncture impact properties is analyzed in combination with two different flexible matrix materials. Furthermore, the potential of the knitted structures in flexible composites is compared to a woven fabric and comprehensively discussed. The tear resistance and the total absorbed energy in puncture impact tests were unaffected by the matrix material. Among the knitted structures, the highest tensile strength, tear resistance and impact properties were achieved with the interlock structure, whereas the double jersey with tuck stitch structure resulted in the lowest flexural modulus. However, a much higher tensile strength was achieved with the woven fabric, at the expense of a higher flexural modulus. Overall, knitted structures proved promising to be used in bio-based flexible composites for applications requiring high flexibility without the need for high tensile strength.

BackgroundSimultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) is a novel hybrid imaging method integrating the advances of morphological tissue characterization of MRI with the pathophysiological insights of PET applications.AimThis study evaluated the use of simultaneous 18-FDG PET/MR imaging for characterizing atherosclerotic lesions in lower extremity arterial disease (LEAD).MethodsEight patients with symptomatic stenoses of the superficial femoral artery (SFA) under simultaneous acquisition of 18-FDG PET and contrast-enhanced MRI using an integrated whole-body PET/MRI scanner. Invasive plaque characterization of the SFA was performed by intravascular imaging using optical coherence tomography. Histological analysis of plaque specimens was performed after directional atherectomy.ResultsMRI showed contrast enhancement at the site of arterial stenosis, as assessed on T2-w and T1-w images, compared to a control area of the contralateral SFA (0.38 ± 0.15 cm vs. 0.23 ± 0.11 cm; 1.77 ± 0.19 vs. 1.57 ± 0.15; p-value 1) at the level of symptomatic stenosis was observed in all but one patient. Contrast medium-induced MR signal enhancement was detected in all plaques, whereas FDG uptake in PET imaging was increased in lesions with active fibroatheroma and reduced in fibrocalcified lesions.ConclusionIn this multimodal imaging study, we report the feasibility and challenges of simultaneous PET/MR imaging of LEAD, which might offer new perspectives for risk estimation.

In this work, the concept of fracture toughness improvement via spatial variation of mechanical properties is applied to a composite with 100% bio-based carbon content based on epoxidized linseed oil. By proper selection of the hardener, either citric acid or sebacic acid, the mechanical properties were adjusted in a way that a bio-composite exhibits a stiff-soft-stiff layer architecture. Samples with two different thicknesses of soft interlayer (approx. 0.1 mm and 1.3 mm) were subsequently analyzed regarding their final performance. Specimen characteristics, owing to the curing and manufacturing process, were analyzed by means of local Fourier-transform infrared spectroscopy and differential scanning calorimetry. Fracture mechanics tests were performed to verify if the soft interlayer acts as a crack arrester. The results propose a high chemical compatibility between the used epoxy resins. Embedding a soft thin interlayer into a stiff resin matrix led to an increase in fracture toughness of 13 times, compared to the pure stiff resin. An increase in interlayer thickness led to a further increase in fracture toughness of 24 times. However, the stiffness decreased by 44% and 67%, respectively.

Abstract In the last decades, our understanding of the role of the immune system in cancer has significantly improved and led to the discovery of new immunotherapeutic targets and tools, which boosted the advances in cancer immunotherapy to fight a growing number of malignancies. Approved immunotherapeutic approaches are currently mainly based on immune checkpoint inhibitors, antibody-derived targeted therapies, or cell-based immunotherapies. In essence, these therapies induce or enhance the infiltration and function of tumor-reactive T cells within the tumors, ideally resulting in complete tumor eradication. While the clinical application of immunotherapies has shown great promise, these therapies are often accompanied either by a variety of side effects as well as partial or complete unresponsiveness of a number of patients. Since different stages of disease progression elicit different local and systemic immune responses, the ability to longitudinally interrogate the migration and expansion of immune cells, especially T cells, throughout the whole body might greatly facilitate disease characterization and understanding. Furthermore, it can serve as a tool to guide development as well as selection of appropriate treatment regiments. This review provides an overview about a variety of immune-imaging tools available to characterize and study T-cell responses induced by anti-cancer immunotherapy. Moreover, challenges are discussed that must be taken into account and overcome to use immune-imaging tools as predictive and surrogate markers to enhance assessment and successful application of immunotherapies.

Abstract Background In the context of nuclear medicine and theranostics, integrin-related research and development was, for most of the time, focused predominantly on 'RGD peptides' and the subtype αvβ3-integrin. However, there are no less than 24 known integrins, and peptides without the RGD sequence as well as non-peptidic ligands play an equally important role as selective integrin ligands. On the other hand, multimerization is a well-established method to increase the avidity of binding structures, but multimeric radiopharmaceuticals have not made their way into clinics yet. In this review, we describe how these aspects have been interwoven in the framework of the German Research Foundation's multi-group interdisciplinary funding scheme CRC 824, yielding a series of potent PET imaging agents for selective imaging of various integrin subtypes. Results The gallium-68 chelator TRAP was utilized to elaborate symmetrical trimers of various peptidic and non-peptidic integrin ligands. Preclinical data suggested a high potential of the resulting Ga-68-tracers for PET-imaging of the integrins α5β1, αvβ8, αvβ6, and αvβ3. For the first three, we provide some additional immunohistochemistry data in human cancers, which suggest several future clinical applications. Finally, application of αvβ3- and αvβ6-integrin tracers in pancreatic carcinoma patients revealed that unlike αvβ3-targeted PET, αvβ6-integrin PET is not characterized by off-target uptake and thus, enables a substantially improved imaging of this type of cancer. Conclusions Novel radiopharmaceuticals targeting a number of different integrins, above all, αvβ6, have proven their clinical potential and will play an increasingly important role in future theranostics.

Abstract Correlation of in vivo imaging to histomorphological pathology in animal models requires comparative interdisciplinary expertise of different fields of medicine. From the morphological point of view, there is an urgent need to improve histopathological evaluation in animal model-based research to expedite translation into clinical applications. While different other fields of translational science were standardized over the last years, little was done to improve the pipeline of experimental pathology to ensure reproducibility based on pathological expertise in experimental animal models with respect to defined guidelines and classifications. Additionally, longitudinal analyses of preclinical models often use a variety of imaging methods and much more attention should be drawn to enable for proper co-registration of in vivo imaging methods with the ex vivo morphological read-outs. Here we present the development of the Comparative Experimental Pathology (CEP) unit embedded in the Institute of Pathology of the Technical University of Munich during the Collaborative Research Center 824 (CRC824) funding period together with selected approaches of histomorphological techniques for correlation of in vivo imaging to morphomolecular pathology.

Abstract 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 VH/VL 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 (KD = 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 89Zr(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.

Abstract Evaluation of treatment response is among the major challenges in modern oncology. We herein used a monoclonal antibody targeting the EGF receptor (EGFR) labelled with the alpha emitter 213Bi (213Bi-anti-EGFR-MAb). EJ28Luc (bladder) and LN18 (glioma) cancer cells, both overexpressing EGFR, were incubated for 3 h with the radioimmunoconjugate. To assess the responses in the core carbon metabolism upon this treatment, these cancer cell lines were subsequently cultivated for 18 h in the presence of [U-13C6]glucose. 13C-enrichment and isotopologue profiles of key amino acids were monitored by gas chromatography–mass spectrometry (GC/MS), in order to monitor the impacts of the radionuclide-treatment upon glucose metabolism. In comparison to untreated controls, treatment of EJ28Luc cells with 213Bi-anti-EGFR-MAb resulted in a significantly decreased incorporation of 13C from [U-13C6]glucose into alanine, aspartate, glutamate, glycine, proline and serine. In sharp contrast, the same amino acids did not display less 13C-enrichments during treatment of the LN18 cells. The data indicate early treatment response of the bladder cancer cells, but not of the glioma cells though cell lines were killed following 213Bi-anti-EGFR-MAb treatment. The pilot study shows that the 13C-labelling approach is a valid tool to assess the responsiveness of cancer cells upon radionuclide-treatment in considerable metabolic detail.

Abstract Introduction The radiohybrid (rh) prostate-specific membrane antigen (PSMA)-targeted ligand [18F]Ga-rhPSMA-7 has previously been clinically assessed and demonstrated promising results for PET-imaging of prostate cancer. The ligand is present as a mixture of four stereoisomers ([18F]Ga-rhPSMA-7.1, − 7.2, − 7.3 and − 7.4) and after a preclinical isomer selection process, [18F]Ga-rhPSMA-7.3 has entered formal clinical trials. Here we report on the establishment of a fully automated production process for large-scale production of [18F]Ga-rhPSMA-7/ -7.3 under GMP conditions (EudraLex). Methods [18F]Fluoride in highly enriched [18O]H2O was retained on a strong anion exchange cartridge, rinsed with anhydrous acetonitrile and subsequently eluted with a solution of [K+ ⊂ 2.2.2]OH− in anhydrous acetonitrile into a reactor containing Ga-rhPSMA ligand and oxalic acid in DMSO. 18F-for-19F isotopic exchange at the Silicon-Fluoride Acceptor (SiFA) was performed at room temperature, followed by dilution with buffer and cartridge-based purification. Optimum process parameters were determined on the laboratory scale and thereafter implemented into an automated synthesis. Data for radiochemical yield (RCY), purity and quality control were analyzed for 243 clinical productions (160 for [18F]Ga-rhPSMA-7; 83 for [18F]Ga-rhPSMA-7.3). Results The automated production of [18F]Ga-rhPSMA-7 and the single isomer [18F]Ga-rhPSMA-7.3 is completed in approx. 16 min with an average RCY of 49.2 ± 8.6% and an excellent reliability of 98.8%. Based on the different starting activities (range: 31–130 GBq, 89 ± 14 GBq) an average molar activity of 291 ± 62 GBq/μmol (range: 50–450 GBq/μmol) was reached for labeling of 150 nmol (231 μg) precursor. Radiochemical purity, as measured by radio-high performance liquid chromatography and radio-thin layer chromatography, was 99.9 ± 0.2% and 97.8 ± 1.0%, respectively. Conclusion This investigation demonstrates that 18F-for-19F isotopic exchange is well suited for the fast, efficient and reliable automated routine production of 18F-labeled PSMA-targeted ligands. Due to its simplicity, speed and robustness the development of further SiFA-based radiopharmaceuticals is highly promising and can be of far-reaching importance for future theranostic concepts.

Abstract The in vivo assessment of tissue metabolism represents a novel strategy for the evaluation of oncologic disease. Hepatocellular carcinoma (HCC) is a high-prevalence, high-mortality tumor entity often discovered at a late stage. Recent evidence indicates that survival differences depend on metabolic alterations in tumor tissue, with particular focus on glucose metabolism and lactate production. Here, we present an in vivo imaging technique for metabolic tumor phenotyping in rat models of HCC. Endogenous HCC was induced in Wistar rats by oral diethyl-nitrosamine administration. Peak lactate-to-alanine signal ratios (L/A) were assessed with hyperpolarized magnetic resonance spectroscopic imaging (HPMRSI) after [1-13C]pyruvate injection. Cell lines were derived from a subset of primary tumors, re-implanted in nude rats, and assessed in vivo with dynamic hyperpolarized magnetic resonance spectroscopy (HPMRS) after [1-13C]pyruvate injection and kinetic modelling of pyruvate metabolism, taking into account systemic lactate production and recirculation. For ex vivo validation, enzyme activity and metabolite concentrations were spectroscopically quantified in cell and tumor tissue extracts. Mean peak L/A was higher in endogenous HCC compared to non-tumorous tissue. Dynamic HPMRS revealed higher pyruvate-to-lactate conversion rates (k pl ) and lactate signal in subcutaneous tumors derived from high L/A tumor cells, consistent with ex vivo measurements of higher lactate dehydrogenase (LDH) levels in these cells. In conclusion, HPMRS and HPMRSI reveal distinct tumor phenotypes corresponding to differences in glycolytic metabolism in HCC tumor tissue.

Introduction and ObjectivesWound healing after myocardial infarction (MI) is a dynamic and complex multiple phase process, and a coordinated cellular response is required for proper scar formation. The current paradigm suggests that pro-inflammatory monocytes infiltrate the MI zone during the initial pro-inflammatory phase and differentiate into inflammatory macrophages, and then switch their phenotypes to anti-inflammatory during the reparative phase. Visualization of the reparative phase post-MI is of great interest because it may reveal delayed resolution of inflammation, which in turn predicts adverse cardiac remodeling. Imaging of anti-inflammatory macrophages may also be used to assess therapy approaches aiming to modulate the inflammatory response in order to limit MI size. Reparative macrophages can be distinguished from inflammatory macrophages by the surface marker mannose receptor (MR, CD206). In this study we evaluated the feasibility of 68Ga-NOTA-anti-MMR Nb for imaging of MR on alternatively activated macrophages in murine MI models.MethodsWildtype and MR-knockout mice and Wistar rats were subjected to MI via permanent ligation of the left coronary artery. Non-operated or sham-operated animals were used as controls. MR expression kinetics on cardiac macrophages was measured in mice using flow cytometry. PET/CT scans were performed 1 h after intravenous injection of 68Ga-NOTA-anti-MMR Nb. Mice and rats were euthanized and hearts harvested for ex vivo PET/MRI, autoradiography, and staining. As a non-targeting negative control, 68Ga-NOTA-BCII10 was used.ResultsIn vivo-PET/CT scans showed focal radioactivity signals in the infarcted myocardium for 68Ga-NOTA-anti-MMR Nb which were confirmed by ex vivo-PET/MRI scans. In autoradiography images, augmented uptake of the tracer was observed in infarcts, as verified by the histochemistry analysis. Immunofluorescence staining demonstrated the presence and co-localization of CD206- and CD68-positive cells, in accordance to infarct zone. No in vivo or ex vivo signal was observed in the animals injected with control Nb or in the sham-operated animals. 68Ga-NOTA-anti-MMR Nb uptake in the infarcts of MR-knockout mice was negligibly low, confirming the specificity of 68Ga-NOTA-anti-MMR Nb to MR.ConclusionThis exploratory study highlights the potential of 68Ga-NOTA-anti-MMR Nb to image MR-positive macrophages that are known to play a pivotal role in wound healing that follows acute MI.

Abstract Background Rheumatoid arthritis (RA) is one of the most common rheumatic diseases. Joint inflammation and pathological growth of joint cartilage cause swollen and painful joints, which severely diminishes the patients’ life quality. There is no causal treatment. Symptomatic therapies should start as early as possible to take maximal effect. Hence, diagnostic procedures capable of detecting affected joints before the onset of clinical symptoms are highly desirable. We explored the value of PET imaging of integrin subtypes αvβ3 and α5β1 for early detection of RA foci in collagen-induced arthritis (CIA) mouse models. Results Development of RA in CIA mice was monitored by paw scoring, and αvβ3- and α5β1-integrin expression was quantified by μPET using 68Ga-Avebetrin and 68Ga-Aquibeprin. For consecutive sections of selected decalcified joints (knee, ankle), arthritic degeneration and integrin expression were assessed by MOVAT staining and β3/α5 immunohistochemistry (IHC), respectively. β3- and α5-IHC revealed elevated levels of both αvβ3- and α5β1-integrin in arthritic joints. Unlike αvβ3, α5β1 is strongly expressed in the proliferating synovial lining layer, which suggests that its presence is directly related to RA development. For mice with advanced RA (6 weeks after CIA), PET signals for α5β1-integrin were substantially stronger (> 300% of baseline) than that of αvβ3-integrin (

Abstract Background Rupture-prone atherosclerotic plaques are characterized by heavy macrophage infiltration, and the presence of certain macrophage subsets might be a sign for plaque vulnerability. The mannose receptor (MR, CD206) is over-expressed in several types of alternatively activated macrophages. In this study, our objective was to evaluate the feasibility of a Gallium-68 (68Ga)-labelled anti-MR nanobody (68Ga-anti-MMR Nb) for the visualization of MR-positive (MR+) macrophages in atherosclerotic plaques of apolipoprotein E-knockout (ApoE-KO) mice. Results NOTA-anti-MMR Nb was labelled with 68Ga with radiochemical purity > 95%. In vitro cell-binding studies demonstrated selective and specific binding of the tracer to M2a macrophages. For in vivo atherosclerotic plaque imaging studies, 68Ga-NOTA-anti-MMR Nb was injected into ApoE-KO and control mice intravenously (i.v.) and scanned 1 h post-injection for 30 min using a dedicated animal PET/CT. Focal signals could be detected in aortic tissue of ApoE-KO mice, whereas no signal was detected in the aortas of control mice. 68Ga-NOTA-anti-MMR Nb uptake was detected in atherosclerotic plaques on autoradiographs and correlated well with Sudan-IV-positive areas. The calculated ratio of plaque-to-normal aortic tissue autoradiographic signal intensity was 7.7 ± 2.6 in aortas excised from ApoE-KO mice. Immunofluorescence analysis of aorta cross-sections confirmed predominant MR expression in macrophages located in the fibrous cap layer and shoulder region of the plaques. Conclusions 68Ga-NOTA-anti-MMR Nb allows non-invasive PET/CT imaging of MR expression in atherosclerotic lesions in a murine model and may represent a promising tool for clinical imaging and evaluation of plaque (in)stability.

The potential of cancer drugs is not fully exploited due to low tumor uptake and occurrence of systemic side effects, limiting maximum tolerated dose. Actively targeted nanocarriers improve efficacy while minimizing off‐target toxicity. Herein, it is the first time a drug‐delivery platform for heat‐triggered intravascular drug release is described, based on synthetic phosphatidyl‐(oligo)‐glycerols from organic synthesis to preclinical investigation in feline patients. For the nanocarrier formulated doxorubicin (DOX), superior tumor drug delivery and antitumor activity compared with free DOX, conventional liposomal DOX (Caelyx), and temperature‐sensitive lysolipid‐containing DOX‐liposomes in rat sarcoma are demonstrated. In a comparative oncological study with neoadjuvant treatment of feline sarcoma, a metabolic response determined with 18 F‐FDG‐positron emission tomography/magnetic resonance imaging (PET/MRI) and histopathological response after tumor resection are significantly better compared with free DOX, potentially by overcoming drug resistance based on improved intratumoral drug distribution. This novel drug‐delivery platform has great potential for the treatment of locally advanced tumors in humans.

Previous unimodal PET and fMRI studies in humans revealed a reproducible vestibular brain activation pattern, but with variations in its weighting and expansiveness. Hybrid studies minimizing methodological variations at baseline conditions are rare and still lacking for task-based designs. Thus, we applied for the first time hybrid 3T PET-MRI scanning (Siemens mMR) in healthy volunteers using galvanic vestibular stimulation (GVS) in healthy volunteers in order to directly compare H215O-PET and BOLD MRI responses. List mode PET acquisition started with the injection of 750 MBq H215O simultaneously to MRI EPI sequences. Group-level statistical parametric maps were generated for GVS vs. rest contrasts of PET, MR-onset (event-related), and MR-block. All contrasts showed a similar bilateral vestibular activation pattern with remarkable proximity of activation foci. Both BOLD contrasts gave more bilateral wide-spread activation clusters than PET; no area showed contradictory signal responses. PET still confirmed the right-hemispheric lateralization of the vestibular system, whereas BOLD-onset revealed only a tendency. The reciprocal inhibitory visual-vestibular interaction concept was confirmed by PET signal decreases in primary and secondary visual cortices, and BOLD-block decreases in secondary visual areas. In conclusion, MRI activation maps contained a mixture of CBF measured using H215O-PET and additional non-CBF effects, and the activation-deactivation pattern of the BOLD-block appears to be more similar to the H215O-PET than the BOLD-onset.

Objective: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of synucleinopathies such as Parkinson’s disease (PD). Positron emission tomography (PET) with 18F-FDG reveals metabolic perturbations, which are scored by spatial covariance analysis. However, the resultant pattern scores do not capture the spatially heterogeneous trajectories of metabolic changes between individual brain regions. Assuming metabolic progression occurs as a continuum from the healthy control (HC) condition to iRBD and then PD, we investigated spatial dynamics of progressively perturbed glucose metabolism in a cross-sectional study. Methods: 19 iRBD patients, 38 PD patients and 19 HC subjects underwent 18F-FDG PET. The images were spatially normalized, scaled to the global mean uptake, and automatically parcellated. We contrasted regional metabolism by group, and allocated the inferred progression to one of several possible trajectories. We further investigated the correlations between 18F-FDG uptake and the disease duration in the iRBD and PD groups, respectively. We also explored relationships between 18F-FDG uptake and the Unified Parkinson’s Disease Rating Scale motor (UPDRS III) scores in the PD group. Results: PD patients exhibited more extensive relative hyper- and hypo-metabolism than iRBD patients. We identified three dynamic metabolic trajectories, cross-sectional hypo- or hypermetabolism, cross-sectionally unchanged hypo- or hypermetabolism, cross-sectionally late hypo- or hypermetabolism, appearing only in the contrast of PD with iRBD. No correlation was found between relative 18F-FDG metabolism and disease duration in the iRBD group. Regional hyper- and hypo-metabolism in the PD patients correlated with disease duration or clinical UPDRS III scores. Conclusion: Cerebral metabolism changes heterogeneously in a continuum extending from HC to iRBD and PD groups in this preliminary study. The distinctive metabolic trajectories point towards a potential neuroimaging biomarker for conversion of iRBD to frank PD, which should be amenable to advanced pattern recognition analysis in future longitudinal studies.

Introduction: Prospective clinical trials are essential to translate new therapy concepts or rather any scientific development into the medical routine. Besides a sophisticated trial protocol, the success of clinical trials depends on patient recruitment and participation. Patient recruitment remains a challenge and depends on several factors. To get a current picture of the patients’ attitude, we conducted the present survey. Methods: We designed a survey with seven questions, which was given to all oncological patients treated within a timeframe of three months between Mai and July 2017. Participation was voluntary and anonymous. The questionnaire mainly inquires patients’ participation in clinical trials in a university-based setting, their attitude towards clinical trials regarding risks and benefits, and their source of information in this context. Results: 771 patients (1:1 male/female) participated with a median age of 61 years (range 18–91 years) with a response rate of 71.5%. Of all, 17.8% (137/771) were participating in a clinical trial. The most mentioned reason was to serve medical progress and cancer research. Out of the patients not currently participating in a trial, 79 (12.7%, 79/623) refusers named the following main reasons: extensive travel time to the clinic, no therapeutic advantage, and too time-consuming. Out of the patients not offered to take part in a trial, 265 (51.0%, 265/520) would participate if offered. Of all patients, 8.3% (64/771) used the clinics' homepage as a source of information, of those 79.7% (51/64) were satisfied with its content. To enhance patient recruitment strategies, we asked how patients wish to be informed about possible trials: More than half (52.0%) of the questioned patients preferred an individual medical consultation with their physician.We further analyzed the trial participation depending on age, gender, unit, and tumor entity. We could show a significant influence of age (p

Abstract Background CXCR4 is a chemokine receptor frequently overexpressed in invasive breast cancer that has been shown to play a major role in signaling pathways involved in metastasis. The aim of this retrospective analysis was to assess the diagnostic performance of CXCR4-directed PET imaging in patients with breast cancer using the recently introduced CXCR4-targeted PET probe 68Ga-Pentixafor. Results Thirteen patients with first diagnosis of breast cancer, four patients with recurrent disease after primary breast cancer, and one patient with axillary lymph node metastasis of unknown primary underwent CXCR4-targeted PET imaging using 68Ga-Pentixafor. Maximum standardized uptake values (SUVmax) and tumor-to-background (T/B) ratios of tumor lesions were measured and compared with pathological prognostic factors and molecular subtypes. 18F-FDG PET/CT images were available in 8/18 cases and were compared semi-quantitatively. Comparison with CXCR4 expression determined by immunohistochemistry was performed in 7/18 patients. Nine of 13 primary breast cancers were visually detectable on 68Ga-Pentixafor PET images (mean SUVmax of 3.0). The visually undetectable lesions included both cases of invasive lobular carcinoma (ILC) and two cases of invasive carcinoma of no special type (NST) without any hormone receptor and HER2 expression (triple negative). Metastases of recurrent breast cancer and unknown primary cancer were visually detectable in all five cases, exhibiting a mean SUVmax of 3.5. 18F-FDG PET demonstrated higher SUVmax in all patients compared to 68Ga-Pentixafor PET. A correlation between SUVmax obtained from 68Ga-Pentixafor PET and prognostic factors including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status, proliferation index, tumor grade, or molecular subtypes was not observed. Conclusions CXCR4-directed PET imaging in patients with primary and recurrent breast cancer is feasible; however, tumor detectability is significantly lower compared to 18F-FDG PET. Moreover, we did not find any correlation between aforementioned prognostic factors of breast cancer and CXCR4-targeted tracer accumulation. Based on these results in a small patient cohort, CXCR4-targeted PET imaging does not seem to be suitable as a general diagnostic tool for imaging of breast cancer. Future CXCR4 imaging studies should investigate whether this modality might be useful in more specific applications, e.g., in therapeutic approaches especially under the view of current developments in targeted immune cell and immune checkpoint inhibitory therapy.

Abstract Background Several radiolabeled prostate-specific membrane antigen (PSMA) inhibitors based on the lysine-urea-glutamate (KuE) motif as the pharmacophore proved to be suitable tools for PET/SPECT imaging of the PSMA expression in prostate cancer patients. PSMA I&T, a theranostic tracer developed in our group, was optimized through alteration of the peptidic structure in order to increase the affinity to PSMA and internalization in PSMA-expressing tumor cells. However, further structural modifications held promise to improve the pharmacokinetic profile. Results Among the investigated compounds 1–9, the PSMA inhibitors 5 and 6 showed the highest PSMA affinity (lowest IC 50 values) after the introduction of a naphthylalanine modification. The affinity was up to three times higher compared to the reference PSMA I&T. Extended aromatic systems such as the biphenylalanine residue in 4 impaired the interaction with the lipophilic binding pocket of PSMA, resulting in a tenfold lower affinity. The IC 50 of DOTAGA-conjugated 10 was slightly increased compared to the acetylated analog; however, efficient PSMA-mediated internalization and 80% plasma protein binding of 68Ga-10 resulted in effective tumor targeting and low uptake in non-target tissues of LNCaP tumor-bearing CD-1 nu/nu mice at 1 h p.i., as determined by small-animal PET imaging and biodistribution studies. For prolonged tumor retention, the plasma protein binding was increased by insertion of 4-iodo-d-phenylalanine resulting in 97% plasma protein binding and 16.1 ± 2.5% ID/g tumor uptake of 177Lu-11 at 24 h p.i. Conclusions Higher lipophilicity of the novel PSMA ligands 10 and 11 proved to be beneficial in terms of affinity and internalization and resulted in higher tumor uptake compared to the parent compound. Additional combination with para-iodo-phenylalanine in the spacer of ligand 11 elevated the plasma protein binding and enabled sustained tumor accumulation over 24 h, increasing the tumor uptake almost fourfold compared to 177Lu-PSMA I&T. However, high renal uptake remains a drawback and further studies are necessary to elucidate the responsible mechanism behind it.

Abstract Background Characterization of tissue integrity and inflammatory processes after acute myocardial infarction (AMI) using non-invasive imaging is predictive of patient outcome. Quantitative cardiovascular magnetic resonance (CMR) techniques such as native T1 and extracellular volume (ECV) mapping as well as 18F-FDG positron emission tomography (PET) imaging targeting inflammatory cell populations are gaining acceptance, but are often applied without assessing their quantitative potential. Using simultaneously acquired PET/CMR data from patients early after AMI, this study quantitatively compares these three imaging markers and investigates links to blood markers of myocardial injury and systemic inflammatory activity. Methods A total of 25 patients without microvascular obstruction were retrospectively recruited. All imaging was simultaneously performed 5 ± 1 days after revascularization following AMI on an integrated 3T PET/MRI scanner. Native and post-contrast T1 data were acquired using a modified Look-Locker inversion recovery (MOLLI) sequence, ECV maps were calculated using individually sampled hematocrit. 18F-FDG PET was executed after 1 day of dietary preparation, 12 h of fasting, and administration of heparin. ECV, 18F-FDG and native T1 data were compared mutually as well as to peak counts of peripheral blood markers (creatine kinase, creatine kinase-MB, troponin, leukocytes, monocytes) and infarct size. Results High intra-patient correlations of relative ECV, 18F-FDG PET and native T1 signal increases were observed in combination with no inter-patient correlation of maximum absolute values at the infarct center, suggesting well-colocalized but physiologically diverse processes begetting the respective image signals. Comparison of maximum image signals to markers of myocardial damage and systemic inflammation yielded highly significant correlations of ECV to peak creatine kinase-MB and overall infarct size as well as between native T1 and peak monocyte counts. Conclusions Absolute native T1 values at the infarct core early after AMI can be linked to the systemic inflammatory response independent of infarct size. Absolute ECV at the infarct core is related to both infarct size and blood markers of myocardial damage.

Abstract Background Due to its high and consistent expression in prostate cancer (PCa), the prostate-specific membrane antigen (PSMA) represents an ideal target for molecular imaging and targeted therapy using highly specific radiolabeled PSMA ligands. To address the continuously growing clinical demand for 18F-labeled PSMA-probes, we developed two novel Glu-urea-Glu-(EuE)-based inhibitors, EuE-k-18F-FBOA (1) and EuE-k-β-a-18F-FPyl (2), both with optimized linker structure and different 18F-labeled aromatic moieties. The inhibitors were evaluated in a comparative preclinical study with 18F-DCFPyl and 18F-PSMA-1007. Results Radiolabeling procedures allowed preparation of (1) and (2) with high radiochemical yields (67 ± 7 and 53 ± 7%, d.c.) and purity (> 98%). When compared with 18F-DCFPyl (IC50 = 12.3 ± 1.2 nM) and 18F-PSMA-1007 (IC50 = 4.2 ± 0.5 nM), both metabolically stable EuE-based ligands showed commensurable or higher PSMA affinity (IC50 = 4.2 ± 0.4 nM (1), IC50 = 1.1 ± 0.2 nM (2)). Moreover, 1.4- and 2.7-fold higher internalization rates were observed for (1) and (2), respectively, resulting in markedly enhanced tumor accumulation in LNCaP-tumor-bearing mice ((1) 12.7 ± 2.0% IA/g, (2) 13.0° ± 1.0% IA/g vs. 7.3 ± 1.0% IA/g (18F-DCFPyl), 7.1 ± 1.5% IA/g (18F-PSMA-1007), 1 h p.i.). In contrast to (1), (2) showed higher kidney accumulation and delayed clearance kinetics. Due to the high hydrophilicity of both compounds, almost no unspecific uptake in non-target tissue was observed. In contrast, due to the less hydrophilic character (logP = − 1.6) and high plasma protein binding (98%), 18F-PSMA-1007 showed uptake in non-target tissue and predominantly hepatobiliary excretion, whereas, 18F-DCFPyl exhibited pharmacokinetics quite similar to those obtained with (1) and (2). Conclusion Both 18F-labeled EuE-based PSMA ligands showed excellent in vitro and in vivo PSMA-targeting characteristics. The substantially higher tumor accumulation in mice compared to recently introduced 18F-PSMA-1007 and 18F-DCFPyl suggests their high value for preclinical studies investigating the effects on PSMA-expression. In contrast to (2), (1) seems to be more promising for further investigation, due to the more reliable 18F-labeling procedure, the faster clearance kinetics with comparable high tumor uptake, resulting therefore in better high-contrast microPET imaging as early as 1 h p.i.

Abstract Background Amino acid co-infusion for renal protection in endoradiotherapy (ERT) applied as prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) or peptide receptor radionuclide therapy (PRRT) has been shown to cause severe hyperkalemia. The pathophysiology behind the rapid development of hyperkalemia is not well understood. We hypothesized that the hyperkalemia should be associated with metabolic acidosis. Results Twenty-two patients underwent ERT. Prior to the first cycle, excretory kidney function was assessed by mercapto-acetyltriglycine (MAG-3) renal scintigraphy, serum biochemistry, and calculated glomerular filtration rate (eGFR). All patients received co-infusion of the cationic amino acids L-arginine and L-lysine for nephroprotection. Clinical symptoms, electrolytes, and acid-base status were evaluated at baseline and after 4 h. No patient developed any clinically relevant side effects. At baseline, acid base status and electrolytes were normal in all patients. Excretory kidney function was normal or only mildly impaired in all except two patients with stage 3 renal insufficiency. All patients developed hyperkalemia. Base excess and HCO3 − were significantly lower after 4 h. In parallel, mean pH dropped from 7.36 to 7.29. There was a weak association between calculated (r = − 0.21) as well as MAG-3-derived GFR (r = − 0.32) and the rise in potassium after 4 h. Conclusion Amino acid co-infusion during ERT leads to severe metabolic acidosis which induces hyperkalemia by potassium hydrogen exchange. This novel finding implies that commercially available bicarbonate solutions might be an easy therapeutic option to correct metabolic acidosis rapidly.

In this work, we designed, developed, characterized, and investigated a new chelator and its bifunctional derivative for 89Zr labeling and PET-imaging. In a preliminary study, we synthesized two hexadentate chelators named AAZTHAS and AAZTHAG, based on the seven-membered heterocycle AMPED (6-amino-6-methylperhydro-1,4-diazepine) with the aim to increase the rigidity of the 89Zr complex by using N-methyl-N-(hydroxy)succinamide or N-methyl-N-(hydroxy)glutaramide pendant arms attached to the cyclic structure. N-methylhydroxamate groups are the donor groups chosen to efficiently coordinate 89Zr. After in vitro stability tests, we selected the chelator with longer arms, AAZTHAG, as the best complexing agent for 89Zr presenting a stability of 86.4 ± 5.5% in human serum (HS) for at least 72 h. Small animal PET/CT static scans acquired at different time points (up to 24 h) and ex vivo organ distribution studies were then carried out in healthy nude mice (n = 3) to investigate the stability and biodistribution in vivo of this new 89Zr-based complex. High stability in vivo, with low accumulation of free 89Zr in bones and kidneys, was measured. Furthermore, an activated ester functionalized version of AAZTHAG was synthesized to allow the conjugation with biomolecules such as antibodies. The bifunctional chelator was then conjugated to the human anti-HER2 monoclonal antibody Trastuzumab (Tz) as a proof of principle test of conjugation to biologically active molecules. The final 89Zr labeled compound was characterized via radio-HPLC and SDS-PAGE followed by autoradiography, and its stability in different solutions was assessed for at least 4 days.

Abstract CXCR4 belongs to the family of chemokine receptors. Together with its sole known ligand CXCL12 (SDF-1alpha), it has a pivotal role during organogenesis and for homing of hematopoietic stem cells. CXCR4 is overexpressed in various malignancies, and this is often associated with poor prognosis. Therefore, molecular imaging of CXCR4 bears a great potential for diagnostics and selecting patients for CXCR4-directed therapies. The CXCR4-directed positron emission tomography (PET) tracer [68Ga]Pentixafor has been shown to visualize CXCR4 expression in various malignancies in vivo. Whereas this tracer has limitations compared to 18F-Fluorodeoxyglucose ([18F]FDG) in diagnostic PET imaging in peripheral tumour lesions, it might add valuable information in routine diagnostics and response assessment of tumours in close proximity to the central nervous system (CNS) and malignancies within this organ. As a proof-of-concept, we performed [68Ga]Pentixafor PET imaging in a patient with extranodal marginal zone lymphoma (MZL) of the orbital cavities at diagnosis and for post-therapy response assessment. Compared to routinely conducted [18F]FDG PET, the lymphoma lesions determined by magnetic resonance imaging (MRI) showed high tracer accumulation at diagnosis, which decreased upon treatment. We therefore propose that imaging of CXCR4 with [68Ga]Pentixafor is a potential diagnostic tool for tumours close to or within the CNS and suggest this being studied in clinical trials.

Local pH alterations can be manifestations of pathologies such as cancer, inflammation and ischaemia. Here Düwelet al. show hyperpolarized 13C-labelled zymonic acid can be used as a non-invasive probe to map and measure pH in vivo, suggesting it as a candidate for clinical imaging and a diagnostic tool.

Abstract Background The impact of local tumor ablative therapy in oligometastasized prostate cancer (PC) is still under debate. To gain data for this approach, we evaluated oligometastasized PC patients receiving stereotactic body radiotherapy (SBRT) to bone metastases. Methods In this retrospective study, 15 oligometastasized PC patients with a total of 20 bone metastases were evaluated regarding biochemical progression-free survival (PSA-PFS), time to initiation of ADT, and local control rate (LCR). Three patients received concomitant androgen deprivation therapy (ADT). Results The median follow-up after RT was 22.5 months (range 7.0–53.7 months). The median PSA-PFS was 6.9 months (range 1.1–28.4 months). All patients showing a decrease of PSA level after RT of at least factor 10 reveal a PSA-PFS of >12 months. Median PSA-PFS of this sub-group was 23.1 months (range 12.1–28.4 months). Local PFS (LPFS) after 2 years was 100%. One patient developed a local failure after 28.4 months. Median distant PFS (DPFS) was 7.36 months (range 1.74–54.34 months). The time to initiation of ADT in patients treated without ADT was 9.3 months (range 2.6–36.1 months). In all patients, the time to intensification of systemic therapy or the time to initiation of ADT increased from 9.3 to 12.3 months (range 2.6–36.1 months). Gleason-Score, ADT or the localization of metastasis had no impact on PFS or time to intensification of systemic therapy. No SBRT related acute or late toxicities were observed. Conclusion Our study shows that SBRT of bone metastases is a highly effective therapy with an excellent risk-benefit profile. However, PFS was limited due to a high distant failure rate implying the difficulty for patient selection for this oligometastatic concept. SBRT offers high local cancer control rates in bone oligometastases of PC and should be evaluated with the aim of curation or to delay modification of systemic treatment.

Abstract Background Atherosclerotic plaque phenotypes are classified based on the extent of macrophage infiltration into the lesions, and the presence of certain macrophage subsets might be a sign for plaque vulnerability. The mannose receptor (MR) is over-expressed in activated macrophages. Tilmanocept is a tracer that targets MR and is approved in Europe and the USA for the detection of sentinel lymph nodes. In this study, our aim was to evaluate the potential of 111In-labelled tilmanocept for the detection of MR-positive macrophages in atherosclerotic plaques of apolipoprotein E-knockout (ApoE-KO) mouse model. Methods Tilmanocept was labelled with 111In. The labelling stability and biodistribution of the tracer was first evaluated in control mice (n = 10) 1 h post injection (p.i.). For in vivo imaging studies, 111In-tilmanocept was injected into ApoE-KO (n = 8) and control (n = 8) mice intravenously (i.v.). The mice were scanned 90 min p.i. using a dedicated animal SPECT/CT. For testing the specificity of 111In-tilmanocept uptake in plaques, a group of ApoE-KO mice was co-injected with excess amount of non-labelled tilmanocept. For ex vivo imaging studies, the whole aortas (n = 9 from ApoE-KO and n = 4 from control mice) were harvested free from adventitial tissue for Sudan IV staining and autoradiography. Cryosections were prepared for immunohistochemistry (IHC). Results 111In radiolabelling of tilmanocept provided a yield of greater than 99%. After i.v. injection, 111In-tilmanocept accumulated in vivo in MR-expressing organs (i.e. liver and spleen) and showed only low residual blood signal 1 h p.i. MR-binding specificity in receptor-positive organs was demonstrated by a 1.5- to 3-fold reduced uptake of 111In-tilmanocept after co-injection of a blocking dose of non-labelled tilmanocept. Focal signal was detected in atherosclerotic plaques of ApoE-KO mice, whereas no signal was detected in the aortas of control mice. 111In-tilmanocept uptake was detected in atherosclerotic plaques on autoradiography correlating well with Sudan IV-positive areas and associating with subendothelial accumulations of MR-positive macrophages as demonstrated by IHC. Conclusions After i.v. injection, 111In-tilmanocept accumulated in MR-expressing organs and was associated with only low residual blood signal. In addition, 111In-tilmanocept uptake was detected in atherosclerotic plaques of mice containing MR-expressing macrophages suggesting that tilmanocept represents a promising tracer for the non-invasive detection of macrophages in atherosclerotic plaques.

Background and purposeThe advantage of combined PET-MRI over sequential PET and MRI is the high spatial conformity and the absence of time delay between the examinations. The benefit of this technique for planning of re-irradiation (re-RT) treatment is unkown yet. Imaging data from a phase 1 trial of re-RT for recurrent glioma was analysed to assess whether planning target volumes and treatment margins in glioma re-RT can be adjusted by PET-MRI with rater independent PET based biological tumour volumes (BTVs).Patients and methodsCombined PET-MRI with the tracer O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) prior to re-RT was performed in recurrent glioma patients in a phase I trial. GTVs including all regions suspicious of tumour on contrast enhanced MRI were delineated by three experienced radiation oncologists and included into MRI based consensus GTVs (MRGTVs). BTVs were semi-automatically delineated with a fixed threshold of 1.6 x background activity. Corresponding BTVs and MRGTVs were fused into union volume PET-MRGTVs. The Sørensen-Dice coefficient and the conformity index were used to assess the geometric overlap of the BTVs with the MRGTVs. A recurrence pattern analysis was performed based on the original planning target volumes (PTVs = GTV + 10 mm margin or 5 mm in one case) and the PET-MRGTVs with margins of 10, 8, 5 and 3 mm.ResultsSeven recurrent glioma patients, who received PET-MRI prior to re-RT, were included into the present planning study. At the time of re-RT, patients were in median 54 years old and had a median Karnofsky Performance Status (KPS) score of 80. Median post-recurrence survival after the beginning of re-RT was 13 months. Concomitant bevacizumab therapy was applied in six patients and one patient received chemoradiation with temozolomide. Median GTV volumes of the three radiation oncologists were 35.0, 37.5 and 40.5 cubic centimeters (cc) and median MRGTV volume 41.8 cc. Median BTV volume was 36.6 cc and median PET-MRGTV volume 59.3 cc. The median Sørensen-Dice coefficient for the comparison between MRGTV and BTV was 0.61 and the median conformity index 0.44. Recurrence pattern analysis revealed two central, two in-field and one distant recurrence within both, the original PTV, as well as the PET-MRGTV with a reduced margin of 3 mm.ConclusionPET-MRI provides radiation treatment planning imaging with high spatial and timely conformity for high-grade glioma patients treated with re-RT with potential advancements for target volume delineation. Prospective randomised trials are warranted to further investigate the treatment benefits of PET-MRI based re-RT planning.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Abstract CXCR4 is a G‐protein‐coupled receptor that mediates recruitment of blood cells toward its ligand SDF‐1. In cancer, high CXCR4 expression is frequently associated with tumor dissemination and poor prognosis. We evaluated the novel CXCR4 probe [68Ga]Pentixafor for in vivo mapping of CXCR4 expression density in mice xenografted with human CXCR4‐positive MM cell lines and patients with advanced MM by means of positron emission tomography (PET). [68Ga]Pentixafor PET provided images with excellent specificity and contrast. In 10 of 14 patients with advanced MM [68Ga]Pentixafor PET/CT scans revealed MM manifestations, whereas only nine of 14 standard [18F]fluorodeoxyglucose PET/CT scans were rated visually positive. Assessment of blood counts and standard CD34+ flow cytometry did not reveal significant blood count changes associated with tracer application. Based on these highly encouraging data on clinical PET imaging of CXCR4 expression in a cohort of MM patients, we conclude that [68Ga]Pentixafor PET opens a broad field for clinical investigations on CXCR4 expression and for CXCR4‐directed therapeutic approaches in MM and other diseases.

Following publication of the original article [1], the authors have reported an error in the ‘Histopathology’ (under ‘Materials and methods’) section of the article that compromises the reproducibility of the paper.

Acute myeloid leukemia originates from leukemia-initiating cells that reside in the protective bone marrow niche. CXCR4/CXCL12 interaction is crucially involved in recruitment and retention of leukemia-initiating cells within this niche. Various drugs targeting this pathway have entered clinical trials. To evaluate CXCR4 imaging in acute myeloid leukemia, we first tested CXCR4 expression in patient-derived primary blasts. Flow cytometry revealed that high blast counts in patients with acute myeloid leukemia correlate with high CXCR4 expression. The wide range of CXCR4 surface expression in patients was reflected in cell lines of acute myeloid leukemia. Next, we evaluated the CXCR4-specific peptide Pentixafor by positron emission tomography imaging in mice harboring CXCR4 positive and CXCR4 negative leukemia xenografts, and in 10 patients with active disease. [68Ga]Pentixafor-positron emission tomography showed specific measurable disease in murine CXCR4 positive xenografts, but not when CXCR4 was knocked out with CRISPR/Cas9 gene editing. Five of 10 patients showed tracer uptake correlating well with leukemia infiltration assessed by magnetic resonance imaging. The mean maximal standard uptake value was significantly higher in visually CXCR4 positive patients compared to CXCR4 negative patients. In summary, in vivo molecular CXCR4 imaging by means of positron emission tomography is feasible in acute myeloid leukemia. These data provide a framework for future diagnostic and theranostic approaches targeting the CXCR4/CXCL12-defined leukemia-initiating cell niche.

INTRODUCTION:To understand if and which patients would be open-minded to Complementary and Alternative Medicine (CAM) use parallel to their oncological treatment. Moreover, we sought to determine which methods are most accepted and which are the primary motivators to use CAM. METHODS:We developed and anonymously conducted a questionnaire for patients in the oncology center (TU Munich). Questions focus on different CAM methods, previous experiences, and willingness to apply or use CAM when offered in a university-based setting. RESULTS:A total of 171 of 376 patients (37.4% women, 62.0% men, 0.6% unknown) participated. This corresponds to a return rate of 45%. Median age was 64 years (17-87 years). Of all participants, 15.2% used CAM during their oncological therapy; 32.7% have used it in the past. The majority (81.9%) was not using CAM during therapy; 55.5% have not used CAM in the past respectively. The analysis revealed a significant correlation between education and CAM use during therapy (r = 0.18; p = 0.02), and CAM use in the past (r = 0.17; p = 0.04). Of all patients using CAM during therapy, favored methods were food supplements (42.3%), vitamins/minerals (42.3%), massage (34.6%). Motivations are especially the reduction of side effect and stress, the positive effect of certain CAM-treatments on the immune system and tumor therapy. Results showed no difference between women and men. Most patients not having had any experience with CAM complain about the deficiency of information by their treating oncologist (31.4%) as well as missing treatment possibilities (54.3%). CONCLUSION:Since many patients believe in study results demonstrating the efficacy of CAM, it stresses our task to develop innovative study protocols to investigate the outcomes of certain CAM on symptom reduction or other endpoints. Thus, prospective trials and innovative evidence-based treatment concepts to include CAM into high-end oncology is what patients demand and what a modern oncology center should offer.

pH is a tightly regulated physiological parameter that is often altered in diseased states like cancer. The development of biosensors that can be used to non-invasively image pH with hyperpolarized (HP) magnetic resonance spectroscopic imaging has therefore recently gained tremendous interest. However, most of the known HP-sensors have only individually and not comprehensively been analyzed for their biocompatibility, their pH sensitivity under physiological conditions, and the effects of chemical derivatization on their logarithmic acid dissociation constant (pKa). Proteinogenic amino acids are biocompatible, can be hyperpolarized and have at least two pH sensitive moieties. However, they do not exhibit a pH sensitivity in the physiologically relevant pH range. Here, we developed a systematic approach to tailor the pKa of molecules using modifications of carbon chain length and derivatization rendering these molecules interesting for pH biosensing. Notably, we identified several derivatives such as [1-13C]serine amide and [1-13C]-2,3-diaminopropionic acid as novel pH sensors. They bear several spin-1/2 nuclei (13C, 15N, 31P) with high sensitivity up to 4.8 ppm/pH and we show that 13C spins can be hyperpolarized with dissolution dynamic polarization (DNP). Our findings elucidate the molecular mechanisms of chemical shift pH sensors that might help to design tailored probes for specific pH in vivo imaging applications.

Introduction2-Deoxy-2-[18F]fluoro-D-glucose PET/CT is a well-established imaging method for staging, restaging and therapy-control in human medicine. In veterinary medicine, this imaging method could prove to be an attractive and innovative alternative to conventional imaging in order to improve staging and restaging. The aim of this study was both to evaluate the effectiveness of this image-guided method in canine patients with spontaneously occurring cancer as well as to illustrate the dog as a well-suited animal model for comparative oncology.MethodsTen dogs with various malignant tumors were included in the study and underwent a whole body FDG PET/CT. One patient has a second PET-CT 5 months after the first study. Patients were diagnosed with histiocytic sarcoma (n = 1), malignant lymphoma (n = 2), mammary carcinoma (n = 4), sertoli cell tumor (n = 1), gastrointestinal stromal tumor (GIST) (n = 1) and lung tumor (n = 1). PET/CT data were analyzed with the help of a 5-point scale in consideration of the patients' medical histories.ResultsIn seven of the ten dogs, the treatment protocol and prognosis were significantly changed due to the results of FDG PET/CT. In the patients with lymphoma (n = 2) tumor extent could be defined on PET/CT because of increased FDG uptake in multiple lymph nodes. This led to the recommendation for a therapeutic polychemotherapy as a treatment. In one of the dogs with mammary carcinoma (n = 4) and in the patient with the lung tumor (n = 1), surgery was cancelled due to the discovery of multiple metastasis. Consequently no treatment was recommended.ConclusionFDG PET/CT offers additional information in canine patients with malignant disease with a potential improvement of staging and restaging. The encouraging data of this clinical study highlights the possibility to further improve innovative diagnostic and staging methods with regard to comparative oncology. In the future, performing PET/CT not only for staging but also in therapy control could offer a significant improvement in the management of dogs with malignant tumors.

Diffusion-weighted magnetic resonance imaging (DW-MRI) and imaging of glucose metabolism by positron emission tomography (FDG-PET) provide quantitative information on tissue characteristics. Combining the two methods might provide novel insights into tumor heterogeneity and biology. Here, we present a solution to analyze and visualize the relationship between the apparent diffusion coefficient (ADC) and glucose metabolism on a spatially resolved voxel-by-voxel basis using dedicated quantitative software.In 12 patients with non small cell lung cancer (NSCLC), the primary tumor or metastases were examined with DW-MRI and PET using 18F-fluorodeoxyglucose (FDG). The ADC's from DW-MRI were correlated with standardized-uptake-values on a voxel-by-voxel basis using custom made software (Anima M3P). For cluster analysis, we used prospectively defined thresholds for 18F-FDG and ADC to define tumor areas of different biological activity.Combined analysis and visualization of ADC maps and PET data was feasible in all patients. Spatial analysis showed relatively homogeneous ADC values over the entire tumor area, whereas FDG showed a decreasing uptake towards the tumor center. As expected, restricted water diffusivity was notable in areas with high glucose metabolism but was also found in areas with lower glucose metabolism. In detail, 72% of all voxels showed low ADC values (3.6). However, 83% of the voxels with low FDG uptake also showed low ADC values, increasingly towards the tumor center.Multiparametric analysis and visualization of DW-MRI and FDG-PET is feasible on a spatially resolved voxel-by-voxel respectively cluster basis using dedicated imaging software. Our preliminary data suggest that water diffusivity and glucose metabolism in metastatic NSCLC are not necessarily correlated in all tumor areas.

Hyperpolarized 13C imaging allows real-time in vivo measurements of metabolite levels. Quantification of metabolite conversion between [1-13C]pyruvate and downstream metabolites [1-13C]alanine, [1-13C]lactate, and [13C]bicarbonate can be achieved through kinetic modeling. Since pyruvate interacts dynamically and simultaneously with its downstream metabolites, the purpose of this work is the determination of parameter values through a multisite, dynamic model involving possible biochemical pathways present in MR spectroscopy. Kinetic modeling parameters were determined by fitting the multisite model to time-domain dynamic metabolite data. The results for different pyruvate doses were compared with those of different two-site models to evaluate the hypothesis that for identical data the uncertainty of a model and the signal-to-noise ratio determine the sensitivity in detecting small physiological differences in the target metabolism. In comparison to the two-site exchange models, the multisite model yielded metabolic conversion rates with smaller bias and smaller standard deviation, as demonstrated in simulations with different signal-to-noise ratio. Pyruvate dose effects observed previously were confirmed and quantified through metabolic conversion rate values. Parameter interdependency allowed an accurate quantification and can therefore be useful for monitoring metabolic activity in different tissues.

Anticalins are a novel class of targeted protein therapeutics. The PEGylated Anticalin Angiocal (PRS-050-PEG40) is directed against VEGF-A. The purpose of our study was to compare the performance of diffusion weighted imaging (DWI), dynamic contrast enhanced magnetic resonance imaging (DCE)-MRI and positron emission tomography with the tracer [18F]fluorodeoxyglucose (FDG-PET) for monitoring early response to antiangiogenic therapy with PRS-050-PEG40. 31 mice were implanted subcutaneously with A673 rhabdomyosarcoma xenografts and underwent DWI, DCE-MRI and FDG-PET before and 2 days after i.p. injection of PRS-050-PEG40 (n = 13), Avastin (n = 6) or PBS (n = 12). Tumor size was measured manually with a caliper. Imaging results were correlated with histopathology. In the results, the tumor size was not significantly different in the treatment groups when compared to the control group on day 2 after therapy onset (P = 0.09). In contrast the imaging modalities DWI, DCE-MRI and FDG-PET showed significant differences between the therapeutic compared to the control group as early as 2 days after therapy onset (P

We recently demonstrated tumor-selective iodide uptake and therapeutic efficacy of combined radiovirotherapy after systemic delivery of the theranostic sodium iodide symporter (NIS) gene using a dendrimer-coated adenovirus. To further improve shielding and targeting we physically coated replication-selective adenoviruses carrying the hNIS gene with a conjugate consisting of cationic poly(amidoamine) (PAMAM) dendrimer linked to the peptidic, epidermal growth factor receptor (EGFR)-specific ligand GE11. In vitro experiments demonstrated coxsackie-adenovirus receptor-independent but EGFR-specific transduction efficiency. Systemic injection of the uncoated adenovirus in a liver cancer xenograft mouse model led to high levels of NIS expression in the liver due to hepatic sequestration, which were significantly reduced after coating as demonstrated by 123I-scintigraphy. Reduction of adenovirus liver pooling resulted in decreased hepatotoxicity and increased transduction efficiency in peripheral xenograft tumors. 124I-PET-imaging confirmed EGFR-specificity by significantly lower tumoral radioiodine accumulation after pretreatment with the EGFR-specific antibody cetuximab. A significantly enhanced oncolytic effect was observed following systemic application of dendrimer-coated adenovirus that was further increased by additional treatment with a therapeutic dose of 131I. These results demonstrate restricted virus tropism and tumor-selective retargeting after systemic application of coated, EGFR-targeted adenoviruses therefore representing a promising strategy for improved systemic adenoviral NIS gene therapy.

In vivo imaging and quantification of amyloid-β plaque (Aβ) burden in small-animal models of Alzheimer's disease (AD) is a valuable tool for translational research such as developing specific imaging markers and monitoring new therapy approaches. Methodological constraints such as image resolution of positron emission tomography (PET) and lack of suitable AD models have limited the feasibility of PET in mice. In this study, we evaluated a feasible protocol for PET imaging of Aβ in mouse brain with [(11)C]PiB and specific activities commonly used in human studies. In vivo mouse brain MRI for anatomical reference was acquired with a clinical 1.5 T system. A recently characterized APP/PS1 mouse was employed to measure Aβ at different disease stages in homozygous and hemizygous animals. We performed multi-modal cross-validations for the PET results with ex vivo and in vitro methodologies, including regional brain biodistribution, multi-label digital autoradiography, protein quantification with ELISA, fluorescence microscopy, semi-automated histological quantification and radioligand binding assays. Specific [(11)C]PiB uptake in individual brain regions with Aβ deposition was demonstrated and validated in all animals of the study cohort including homozygous AD animals as young as nine months. Corresponding to the extent of Aβ pathology, old homozygous AD animals (21 months) showed the highest uptake followed by old hemizygous (23 months) and young homozygous mice (9 months). In all AD age groups the cerebellum was shown to be suitable as an intracerebral reference region. PET results were cross-validated and consistent with all applied ex vivo and in vitro methodologies. The results confirm that the experimental setup for non-invasive [(11)C]PiB imaging of Aβ in the APP/PS1 mice provides a feasible, reproducible and robust protocol for small-animal Aβ imaging. It allows longitudinal imaging studies with follow-up periods of approximately one and a half years and provides a foundation for translational Alzheimer neuroimaging in transgenic mice.

Positron emission tomography-computed tomography (PET-CT) is superior compared to stand-alone PET in evaluation of malignancies. Few studies have employed high-resolution structural information to correct PET. We designed a semiautomatic algorithm using CT and PET to obtain a partial volume corrected (PVC) standardized uptake value (SUV) and a combined morphologic and functional parameter (multimodal SUV) for lymph node assessment. Lesions were segmented by a semiautomatic algorithm in CT images. Lesion volume was used for PVC and for calculating the multimodal SUV. The method was applied to 47 lymph nodes (30 patients) characterized as suspicious in 18 F-fluorodeoxyglucose-PET-CT. In phantoms, PVC improved significantly the measured uptake of the lesion. In patients, 36 lymph nodes could be segmented without problems; in 11 lesions, a manual interaction was necessary. SUVs before PVC (mean 1.29) increased significantly ( p < .0005) after PVC (mean 2.8). If SUV 2.5 was used as a threshold value to distinguish between benign and malignant lesions, 11 of the 47 lesions changed from benign to malignant after the PVC. The mean multimodal SUV was 0.39 mL for the benign lesions and 4.47 mL for the malignant lesions. In this work we presented a method for quantitative analysis of lymph nodes in PET-CT. PVC leads to significant differences in SUV.

BackgroundSuccessful cognitive performance depends not only on the activation of specific neuronal networks but also on selective suppression of task-irrelevant modalities, i.e., deactivation of non-required cerebral regions. This ability to suppress the activation of specific brain regions has, to our knowledge, never been systematically evaluated in patients with Alzheimer disease (AD). The aim of the current study was to evaluate both cerebral activation and deactivation in (1) healthy volunteers, (2) patients with mild cognitive impairment (MCI) who are at risk for AD, and (3) patients with moderate AD during active navigation, representing a cognitive task typically affected in AD.Methods and findingsChanges in regional cerebral blood flow (rCBF) were assessed with PET imaging during an active navigation task in a 3D virtual-reality environment. The task was based on visual cues exclusively; no auditory cues were provided. Age-matched groups of healthy individuals, patients with MCI, and patients with AD were examined. Specific differences in the activation patterns were observed in the three groups, with stronger activation of cerebellar portions and visual association cortex in controls and stronger activation of primary visual and frontal cortical areas in patients with MCI and AD. Highly significant bilateral decrease of rCBF in task-irrelevant auditory cortical regions was detected in healthy individuals during performance of the task. This rCBF decrease was interpreted as a cross-modal inhibitory effect. It was diminished in patients with MCI and completely absent in patients with AD. A regression analysis across all individuals revealed a clear positive relation between cognitive status (mini mental state examination score) and the extent of auditory cortical deactivation.ConclusionDuring active navigation, a high level of movement automation and an involvement of higher-order cerebral association functions were observed in healthy controls. Conversely, in patients with MCI and AD, increased cognitive effort and attention towards movement planning, as well as stronger involvement of lower-order cerebral systems, was found. Successful cognitive performance in healthy individuals is associated with deactivation of task-irrelevant cerebral regions, whereas the development of AD appears to be characterized by a progressive impairment of cross-modal cerebral deactivation functions. These changes may cause the generally decreased ability of patients with AD to direct attention primarily to the relevant cognitive modality.

BACKGROUND: The integrin alphavbeta3 plays an important role in angiogenesis and tumor cell metastasis, and is currently being evaluated as a target for new therapeutic approaches. Several techniques are being studied to enable noninvasive determination of alphavbeta3 expression. We developed [(18)F]Galacto-RGD, a (18)F-labeled glycosylated alphavbeta3 antagonist, allowing monitoring of alphavbeta3 expression with positron emission tomography (PET). METHODS AND FINDINGS: Here we show by quantitative analysis of images resulting from a small-animal PET scanner that uptake of [(18)F]Galacto-RGD in the tumor correlates with alphavbeta3 expression subsequently determined by Western blot analyses. Moreover, using the A431 human squamous cell carcinoma model we demonstrate that this approach is sensitive enough to visualize alphavbeta3 expression resulting exclusively from the tumor vasculature. Most important, this study shows, that [(18)F]Galacto-RGD with PET enables noninvasive quantitative assessment of the alphavbeta3 expression pattern on tumor and endothelial cells in patients with malignant tumors. CONCLUSIONS: Molecular imaging with [(18)F]Galacto-RGD and PET can provide important information for planning and monitoring anti-angiogenic therapies targeting the alphavbeta3 integrins and can reveal the involvement and role of this integrin in metastatic and angiogenic processes in various diseases.